Ig free dot net

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Each antibody binds to a specific antigen; an interaction similar to a lock and key.

An antibody ( Ab), also known as an immunoglobulin ( Ig), [1] is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the pathogen, called an antigen. [2] [3] Each tip of the "Y" of an antibody contains a paratope (analogous to a lock) that is specific for one particular epitope (analogous to a key) on an antigen, allowing these two structures to bind together with precision.

Using this binding mechanism, an antibody can tag a microbe or an infected cell for attack by other parts of the immune system, or can neutralize it directly (for example, by blocking a part of a virus that is essential for its invasion). To allow the immune system to recognize millions of different antigens, the antigen-binding sites at both tips of the antibody come in an equally wide variety.

In contrast, the remainder of the antibody is relatively constant. It only occurs in a few variants, which define the antibody's class or isotype: IgA, IgD, IgE, IgG, or IgM. The constant region at the trunk of the antibody includes sites involved in interactions with other components of the immune system. The class hence determines the function triggered by ig free dot net antibody after binding to an antigen, in addition to some structural features.

Antibodies from different classes also differ in where they are released in the body and at what stage of an immune response. Together with B and T cells, antibodies comprise the most important part of the adaptive immune system. They occur in two forms: one that is attached to a B cell, and the other, a soluble form, that is unattached and found in extracellular fluids such as blood plasma. Initially, all antibodies are of the first form, attached to the surface of a B cell – these are then referred to as B-cell receptors (BCR).

After an antigen binds to a BCR, the B cell activates to proliferate and differentiate into either plasma cells, which secrete soluble antibodies with the same paratope, or memory B cells, which survive in the body to enable long-lasting immunity to the antigen. [4] Soluble antibodies are released into the blood and tissue fluids, as well as many secretions. Because these fluids were traditionally known as humors, antibody-mediated immunity is sometimes known as, or considered a part of, humoral immunity.

[5] The soluble Y-shaped units can occur individually as monomers, or in complexes of two to five units. Antibodies are glycoproteins belonging to the immunoglobulin superfamily. The terms antibody and immunoglobulin are often used interchangeably, [1] though the term 'antibody' is sometimes reserved for the secreted, soluble form, i.e.

excluding B-cell receptors. [6] Contents • 1 Structure • 1.1 Antigen-binding site • 1.2 Fc region • 1.3 Protein structure • 1.4 Antibody complexes • 1.5 B cell receptors • 2 Classes • 2.1 Light chain types • 2.2 In non-mammalian animals • 3 Antibody–antigen interactions • 4 Function • 4.1 Activation of complement • 4.2 Activation of effector cells • 4.3 Natural antibodies • 5 Immunoglobulin diversity • 5.1 Domain variability • 5.2 V(D)J recombination • 5.3 Somatic hypermutation and affinity maturation • 5.4 Class switching • 5.5 Specificity designations • 5.6 Asymmetrical antibodies • 6 History ig free dot net 7 Medical applications • 7.1 Disease diagnosis • 7.2 Disease therapy • 7.3 Prenatal therapy • 8 Research applications • 9 Regulations • 9.1 Production and testing • 9.2 Before clinical trials • 9.3 Preclinical studies • 10 Structure prediction and computational antibody design • 11 Antibody mimetic • 11.1 Optimer ligands • 12 Binding antibody unit • 13 See also • 14 References • 15 External links Structure [ edit ] A more accurate depiction of an antibody (3D structure at RCSB PDB).

Glycans in the Fc region are shown in black. Antibodies are heavy (~150 k Da) proteins of about 10 nm in size, [7] arranged in three globular regions that roughly form a Y shape. In humans and most mammals, an antibody unit consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds.

[8] Each chain is a series of domains: somewhat similar sequences of about 110 amino acids each. These domains are usually represented in simplified schematics as rectangles. Light chains consist of one variable domain V L and one constant domain C L, while heavy chains contain one variable domain V H and three to four constant domains C H1, C H2. . [9] Structurally an antibody is also partitioned into two antigen-binding fragments (Fab), containing one V L, V H, C L, and C H1 domain each, as well as the crystallisable fragment (Fc), forming the trunk of the Y shape.

[10] In between them is a hinge region of the heavy chains, whose flexibility allows antibodies to bind to pairs of epitopes at various distances, to form complexes ( dimers, trimers, etc.), and to bind effector molecules more easily. [11] In an electrophoresis test of blood proteins, antibodies mostly migrate to the last, gamma globulin fraction.

Conversely, most gamma-globulins are antibodies, which is why the two terms were historically used as synonyms, as were the symbols Ig and γ. This variant terminology fell out of use due to the correspondence being inexact and due to confusion with γ heavy chains which characterize the IgG class of antibodies.

[12] [13] Antigen-binding site [ edit ] The variable domains can also be referred to as the F V region. It is the subregion of Fab that binds to an antigen. More specifically, each variable domain contains three hypervariable regions – the amino acids seen there vary the most from antibody to antibody. When the protein folds, these regions give rise to three loops of β-strands, localized near one another on the surface of the antibody.

These loops are referred to as the complementarity-determining regions (CDRs), since their shape complements that of an antigen. Three CDRs from each of the heavy and light chains together form an antibody-binding site whose shape can be anything from a pocket to which a smaller antigen binds, to a larger surface, to a protrusion that sticks out into a groove in an antigen. Typically however only a few residues contribute to most of the binding energy.

[2] The existence of two identical antibody-binding sites allows antibody molecules to bind strongly to multivalent antigen (repeating sites such as polysaccharides in bacterial cell walls, or other sites at some distance apart), as well as to form antibody complexes and larger antigen-antibody complexes. [2] The resulting cross-linking plays a role in activating other parts of the immune system.

The structures of CDRs have been clustered and classified by Chothia et al. [14] and more recently by North et al. [15] and Nikoloudis et al. [16] However, describing an antibody's binding site using only one single static structure limits the understanding and characterization of the antibody's function and properties. To improve antibody structure prediction and to take the strongly correlated CDR loop and interface movements into account, antibody paratopes should be described as interconverting states in solution with varying probabilities.

[17] In the framework of the immune network theory, CDRs are also called idiotypes. According to immune network theory, the adaptive immune system is regulated by interactions between idiotypes. Fc region [ edit ] Main article: Fragment crystallizable region The Fc region (the trunk of the Y shape) is composed of constant domains from the heavy chains.

Its role is in modulating immune cell activity: it is where effector molecules bind to, triggering various effects after the antibody Fab region binds to an antigen. [2] [11] Effector cells (such as macrophages or natural killer cells) bind via their Fc receptors (FcR) to the Fc region of an antibody, while the complement system is activated by binding the C1q protein complex. IgG or IgM can bind to C1q, but IgA cannot, therefore IgA does not activate the classical complement pathway.

[18] Another role of the Fc region is to selectively distribute different antibody classes across the body. In particular, the neonatal Fc receptor (FcRn) binds to the Fc region of IgG antibodies to transport it across the placenta, from the mother to the fetus. Antibodies are glycoproteins, [19] that is, they have carbohydrates (glycans) added to conserved amino acid residues.

[19] [20] These conserved glycosylation sites occur in the Fc region and influence interactions with effector molecules. [19] [21] Protein structure [ edit ] The N-terminus of each chain is situated at the tip.

Each immunoglobulin domain has a similar structure, characteristic of all the members of the immunoglobulin superfamily: it is composed of between 7 (for constant domains) and 9 (for variable domains) β-strands, forming two beta sheets in a Greek key motif. The sheets create a "sandwich" shape, the immunoglobulin fold, held together by a disulfide bond. Antibody complexes [ edit ] Some antibodies form complexes that bind to multiple antigen molecules.

Secreted antibodies can occur as a single Y-shaped unit, a monomer. However, some antibody classes also form dimers with two Ig units (as with IgA), tetramers with four Ig units (like teleost fish IgM), or pentamers with five Ig units (like shark IgW or mammalian IgM, which occasionally forms hexamers as well, with six units).

[22] Antibodies also form complexes by binding to antigen: this is called an antigen-antibody complex or immune complex. Small antigens can cross-link two antibodies, also leading to the formation of antibody dimers, trimers, tetramers, etc. Multivalent antigens (e.g., cells with multiple epitopes) can form larger complexes with antibodies. An extreme example is the clumping, or agglutination, of red blood cells with antibodies in the Coombs test to determine blood groups: the large clumps become insoluble, leading to visually apparent precipitation.

B cell receptors [ edit ] Main article: B-cell receptor The membrane-bound form of an antibody may be called a surface immunoglobulin (sIg) or a membrane immunoglobulin (mIg). It is part of the B cell receptor (BCR), which allows a B cell to detect when a specific antigen is present in the body and triggers B cell activation.

[23] The BCR is composed of surface-bound IgD or IgM antibodies and associated Ig-α and Ig-β heterodimers, which are capable of signal transduction. [24] A typical human B cell will have 50,000 to 100,000 antibodies bound to its surface. [24] Upon antigen binding, they cluster in large patches, which can exceed 1 micrometer in diameter, on lipid rafts that isolate the BCRs from most other cell signaling receptors.

[24] These patches may improve the efficiency of the cellular immune response. [25] In humans, the cell surface is bare around the B cell receptors for several hundred nanometers, [24] which further isolates the BCRs from competing influences. Classes [ edit ] Antibodies can come in different varieties known as isotypes or classes. In placental mammals there are five antibody classes known as IgA, IgD, IgE, IgG, and IgM, which are further subdivided into subclasses such as IgA1, IgA2.

The prefix "Ig" stands for immunoglobulin, while the suffix denotes the type of heavy chain the antibody contains: the heavy chain types α (alpha), γ (gamma), δ (delta), ε (epsilon), μ (mu) give rise to IgA, IgG, IgD, IgE, IgM, respectively. The distinctive features of each class are determined by the part of the heavy chain within the hinge and Fc region.

[2] The classes differ in their biological properties, functional locations and ability to deal with different antigens, as depicted in the table. [8] For example, IgE antibodies are responsible for an allergic response consisting of histamine release from mast cells, often a sole contributor to asthma (though other pathways exist as do exist symptoms very similar to yet not technically asthma).

The antibody's variable region binds to allergic antigen, for example house dust mite particles, while its Fc region (in the ε heavy chains) binds to Fc receptor ε on a mast cell, triggering its degranulation: the release of molecules stored in its granules. [26] Antibody isotypes of mammals Class Subclasses Description IgA 2 Found in mucosal areas, such as the gut, respiratory tract and urogenital tract, and prevents colonization by pathogens.

[27] Also found in saliva, tears, and breast milk. IgD 1 Functions mainly as an antigen receptor on B cells that have not been exposed to antigens. [28] It has been shown to activate basophils and mast cells to produce antimicrobial factors. [29] IgE 1 Binds to allergens and triggers histamine release from mast cells and basophils, and is involved in allergy. Humans and other animals evolved IgE to protect against parasitic worms, though in the present, IgE is primarily related to allergies and asthma.

[5] IgG 4 In its four forms, provides the majority of antibody-based immunity against invading pathogens. [5] The only antibody capable of crossing the placenta to give passive immunity to the fetus. IgM 1 Expressed on the surface of Ig free dot net cells (monomer) and in a secreted form (pentamer) with very high avidity. Eliminates pathogens in the early stages of B cell-mediated (humoral) immunity before there ig free dot net sufficient IgG.

[5] [28] The antibody isotype of a B cell changes during cell development and activation. Immature B cells, which have never been exposed to an antigen, express only the IgM isotype in a cell surface bound form. The B lymphocyte, in this ready-to-respond form, is known as a " naive B lymphocyte." The naive B lymphocyte expresses both surface IgM and IgD.

The co-expression of both of these immunoglobulin isotypes renders the B cell ready to respond to antigen. [30] B cell activation follows engagement of the cell-bound antibody molecule with an antigen, causing the cell to divide and differentiate into an antibody-producing cell called a plasma cell. In this activated form, the B cell starts to produce antibody in a secreted form rather than a membrane-bound form. Some daughter cells of the activated B cells undergo isotype switching, a mechanism that causes the production of antibodies to change from IgM or IgD to the other antibody isotypes, IgE, IgA, or IgG, that have defined roles in the immune system.

Light chain types [ edit ] Further information: Immunoglobulin light chain In mammals there are two types of immunoglobulin light chain, which are called lambda (λ) and kappa (κ). However, there is no known functional difference between them, and both can occur with any of the five major types of heavy chains. [2] Each antibody contains two identical light chains: both κ or both λ. Proportions of κ and λ types vary by species and can be used to detect abnormal proliferation of B cell clones.

Other types of light ig free dot net, such as the iota (ι) chain, are found in other vertebrates like sharks ( Chondrichthyes) and bony fishes ( Teleostei). In ig free dot net animals [ edit ] In most placental mammals, the structure of antibodies is generally the same.

Jawed fish appear to be the most primitive animals that are able to make antibodies similar to those of mammals, although many features of their adaptive immunity appeared somewhat earlier. [31] Cartilaginous fish (such as sharks) produce heavy-chain-only antibodies (i.e., lacking light chains) which moreover feature longer chain pentamers (with five constant units per molecule).

Camelids (such as camels, llamas, alpacas) are also notable for producing heavy-chain-only antibodies. [2] [32] Antibody classes not found in mammals Class Types Description IgY Found in birds and reptiles; related to mammalian IgG. [33] IgW Found in sharks and skates; related to mammalian IgD.

[34] IgT/Z Found in teleost fish [35] Ig free dot net interactions [ edit ] The antibody's paratope interacts with the antigen's epitope. An antigen usually contains different epitopes along its surface arranged discontinuously, and dominant epitopes on a given antigen are called determinants.

Antibody and antigen interact by spatial complementarity (lock and key). The molecular forces involved in the Fab-epitope interaction are weak and non-specific – for example electrostatic forces, hydrogen bonds, hydrophobic interactions, and van der Waals forces.

This means binding between antibody and antigen is reversible, and the antibody's affinity towards an antigen is relative rather than absolute. Relatively weak binding also means it is possible for an antibody to cross-react with different antigens of different relative affinities.

Function [ edit ] • opsonization, • neutralisation, and • agglutination. • A phagocyte (C) approaches the pathogen, and the Fc region (D) of the antibody binds to one of ig free dot net Fc receptors (E) of the phagocyte. • Phagocytosis occurs as the ig free dot net is ingested. • Neutralisation, in which neutralizing antibodies block parts of the surface of a bacterial cell or virion to render its attack ineffective • Agglutination, in which antibodies "glue together" foreign cells into clumps that are attractive targets for phagocytosis • Precipitation, in which antibodies "glue together" serum-soluble antigens, forcing them to precipitate out of solution in clumps that are attractive targets for phagocytosis • Complement activation (fixation), in which antibodies that are latched onto a foreign cell encourage complement ig free dot net attack it with a membrane attack complex, which leads to the following: • Lysis of the foreign cell • Encouragement of inflammation by chemotactically attracting inflammatory cells More indirectly, an antibody can signal immune cells to present antibody fragments to T cells, or downregulate other immune cells to avoid autoimmunity.

Activated B cells differentiate into either antibody-producing cells called plasma cells that secrete soluble antibody or memory cells that survive in the body for years afterward in order to allow the immune system to remember an antigen and respond faster upon future exposures.

[4] At the prenatal and neonatal stages of life, the presence of antibodies is provided by passive immunization from the mother. Early endogenous antibody production varies for different kinds of antibodies, and usually appear within the first years of life.

Since antibodies exist freely in the bloodstream, they are said to be part of the humoral immune system. Circulating antibodies are produced by clonal B cells that specifically respond to only one antigen (an example is a virus capsid protein fragment). Antibodies contribute to immunity in three ways: They prevent pathogens from entering or damaging cells by binding to them; they stimulate removal of pathogens by macrophages and other cells by coating the pathogen; and they trigger destruction of pathogens by stimulating other immune responses such as the complement pathway.

[36] Antibodies will also trigger vasoactive amine degranulation to contribute to immunity against certain types of ig free dot net (helminths, allergens). The secreted mammalian IgM has five Ig units. Each Ig unit (labeled 1) has two epitope binding Fab regions, so IgM is capable of binding up to 10 epitopes.

Activation of complement [ edit ] Antibodies that ig free dot net to surface antigens (for example, on bacteria) will attract the first component of the complement cascade with their Fc region and initiate activation of the "classical" complement system.

[36] This results in the killing of bacteria in two ways. [5] First, the binding of the antibody and complement molecules marks the microbe for ingestion by phagocytes in a process called opsonization; these phagocytes are attracted by certain complement molecules generated in the complement cascade.

Second, some complement system components form a membrane attack complex to assist antibodies to kill the bacterium directly (bacteriolysis). [37] Activation of effector cells [ edit ] To combat pathogens that replicate outside cells, antibodies bind to pathogens to link them together, causing them to agglutinate. Since an antibody ig free dot net at least two paratopes, it can bind more than one antigen by binding identical epitopes carried on the surfaces of these antigens.

By coating the pathogen, antibodies stimulate effector functions against the pathogen in cells that recognize their Fc region. [5] Those cells that recognize coated pathogens have Fc receptors, which, as the name suggests, interact with the Fc region of IgA, IgG, and IgE antibodies. The engagement of a particular antibody with the Fc receptor on a particular cell triggers an effector function of that cell; phagocytes will phagocytose, mast cells and neutrophils will degranulate, natural killer cells will release cytokines and cytotoxic molecules; that will ultimately result in destruction of the invading microbe.

The activation of natural killer cells by antibodies initiates a cytotoxic mechanism known as antibody-dependent cell-mediated cytotoxicity (ADCC) – this process may explain the efficacy of monoclonal antibodies used in biological therapies against cancer. The Fc receptors are isotype-specific, which gives greater flexibility to the immune system, invoking only the appropriate immune mechanisms for distinct pathogens. [2] Natural antibodies [ edit ] Humans and higher primates also produce "natural antibodies" that are present in serum before viral infection.

Natural antibodies have been defined as antibodies that are produced without any previous infection, vaccination, other foreign antigen exposure or passive immunization. These antibodies can activate the classical complement pathway leading to lysis of enveloped virus particles long before the adaptive immune response is activated. Many natural antibodies are directed against the disaccharide galactose α(1,3)-galactose (α-Gal), which is found as a terminal sugar on glycosylated cell surface proteins, and generated in response to production of this sugar by bacteria contained in the human gut.

[38] Rejection of xenotransplantated organs is thought to be, ig free dot net part, the result of natural antibodies circulating in the serum of the recipient binding to α-Gal antigens expressed on the donor tissue. [39] Immunoglobulin diversity [ edit ] Virtually all microbes can trigger an antibody response. Successful recognition and eradication of many different ig free dot net of microbes requires diversity among antibodies; their amino acid composition varies allowing them to interact with many different antigens.

[40] It has been estimated that humans generate about 10 billion different antibodies, each capable of binding a distinct epitope of an antigen. [41] Although a huge repertoire of different antibodies is generated in a single individual, the number of genes available to make these proteins is limited by the size of the human genome. Several complex genetic mechanisms have evolved that allow vertebrate B cells to generate a diverse pool of antibodies from a relatively small number of antibody genes.

[42] Domain variability [ edit ] The complementarity determining regions of the heavy chain are shown in red ( PDB: 1IGT​) The chromosomal region that encodes an antibody is large and contains several distinct gene loci for each domain of the antibody—the chromosome region containing heavy chain genes ( IGH@) is found on chromosome 14, and the loci containing lambda and kappa light chain genes ( IGL@ and IGK@) are found on chromosomes 22 and 2 in humans.

One of these domains is called the variable domain, which is present in each heavy and light chain of every antibody, but can differ in different antibodies generated from distinct B cells.

Differences, between the variable domains, are located on three loops known as hypervariable regions (HV-1, HV-2 and HV-3) or complementarity-determining regions (CDR1, CDR2 and CDR3).

CDRs are supported within the variable domains by conserved framework regions. The heavy chain locus contains about 65 different variable domain genes that all differ in their CDRs. Combining these genes with an array of genes for other domains of the antibody generates a large cavalry of antibodies with a high degree of variability.

This combination is called V(D)J recombination discussed below. [43] V(D)J recombination [ edit ] Simplified overview of V(D)J recombination of immunoglobulin heavy chains Somatic recombination of immunoglobulins, also known as V(D)J recombination, involves the generation of a unique immunoglobulin variable region.

The variable region of each immunoglobulin heavy or light chain is encoded in several pieces—known as gene segments (subgenes). These segments are called variable (V), diversity (D) and joining (J) segments.

[42] V, D and J segments are found in Ig heavy chains, but only V and J segments are found in Ig light chains. Multiple copies of the V, D and J gene segments exist, and are tandemly arranged in the genomes of mammals. In the bone marrow, each developing B cell will assemble an immunoglobulin variable region by randomly selecting and combining one V, one D and one J gene segment (or one V and one J segment in the light chain). As there are multiple copies of each type of gene segment, and different combinations of gene segments can be used to generate each immunoglobulin variable region, this process generates a huge number of antibodies, each with different paratopes, and thus different antigen specificities.

[44] The rearrangement of several subgenes (i.e. V2 family) for lambda light chain immunoglobulin is coupled with the activation of microRNA miR-650, which further influences biology of B-cells.

RAG proteins play an important role with V(D)J recombination in cutting DNA at a particular region. [44] Without the presence of these proteins, V(D)J recombination would not occur. [44] After a B cell produces a functional immunoglobulin gene during V(D)J recombination, it cannot express any other variable region (a process known as allelic exclusion) thus each B cell can produce antibodies containing only one kind of variable chain.

[2] [45] Somatic hypermutation and affinity maturation [ edit ] Further information: Somatic hypermutation and Affinity maturation Following activation with antigen, B cells begin to proliferate rapidly.

In these rapidly dividing cells, the genes encoding the variable domains of the heavy and light chains undergo a high rate of point mutation, by a process called somatic hypermutation (SHM). SHM results in approximately one nucleotide change per variable gene, per cell division.

[46] As a consequence, any daughter B cells will acquire slight amino acid differences in the variable domains of their antibody chains. This serves to increase the diversity of the antibody pool and impacts the antibody's antigen-binding affinity.

[47] Some point mutations will result in the production of antibodies that have a weaker interaction (low affinity) with their antigen than the original antibody, and some mutations will generate antibodies with a stronger interaction (high affinity).

[48] B cells that express high affinity antibodies on their surface will receive a strong survival signal during interactions with other cells, whereas those with low affinity antibodies will not, and will die by apoptosis. [48] Thus, B cells expressing antibodies with a higher affinity for the antigen will outcompete those with weaker affinities for function and survival allowing the average affinity of antibodies to increase over time.

The process of generating antibodies with increased binding affinities is called affinity maturation. Affinity maturation occurs in mature B cells after V(D)J recombination, and is dependent on help from helper T cells. [49] Mechanism of class switch recombination that allows isotype switching in activated B cells Class switching [ edit ] Isotype or class switching is a biological process occurring after activation of the B cell, which allows the cell to produce different classes of antibody (IgA, IgE, or IgG).

[44] The different classes of antibody, and thus effector functions, are defined by the constant (C) regions of the immunoglobulin heavy chain. Initially, naive B cells express only cell-surface IgM and IgD with identical antigen binding regions. Each isotype is adapted for a distinct function; therefore, after activation, an antibody with an IgG, IgA, or IgE effector function might be required to effectively eliminate an antigen.

Class switching allows different daughter cells from the same activated Ig free dot net cell to produce antibodies of different isotypes. Only the constant region of the antibody heavy chain changes during class switching; the variable regions, and therefore antigen specificity, remain unchanged.

Thus the progeny of a single B cell can produce antibodies, all specific for the same antigen, but with the ability to produce the effector function appropriate for each antigenic challenge. Class switching is triggered by cytokines; the isotype generated depends on which cytokines are present in the B cell environment.

[50] Class switching occurs in the heavy chain gene locus by a mechanism called class switch recombination (CSR). This mechanism relies on conserved nucleotide motifs, called switch (S) regions, found in DNA upstream of each constant region gene (except in the δ-chain).

The DNA strand is broken by the activity of a series of enzymes at two selected S-regions. [51] [52] The variable domain exon is rejoined through a process called non-homologous end joining (NHEJ) to the desired constant region (γ, α or ε). This process results in an immunoglobulin gene that encodes an antibody of a different isotype. [53] Specificity designations [ edit ] An antibody can be called monospecific if it has specificity for the same antigen or epitope, [54] or bispecific if they have affinity for two different antigens or two different epitopes on the same antigen.

[55] A group of antibodies can be called polyvalent (or unspecific) if they have affinity for various antigens [56] or microorganisms. [56] Intravenous immunoglobulin, if not otherwise noted, consists of a variety of different IgG (polyclonal IgG).

In contrast, monoclonal antibodies are identical antibodies produced by a single B cell. Asymmetrical antibodies [ edit ] Heterodimeric antibodies, which are also asymmetrical antibodies, allow for greater flexibility and new formats for attaching a variety of drugs to the antibody arms.

One of the general formats for a heterodimeric antibody is the "knobs-into-holes" format. This format is specific to the heavy chain part of the constant region in antibodies. The "knobs" part is engineered by replacing a small ig free dot net acid with a larger one. It fits into the "hole", which is engineered by replacing a large amino acid with a smaller one.

What connects the "knobs" to the "holes" are the disulfide bonds between each chain. The "knobs-into-holes" shape facilitates antibody dependent cell mediated cytotoxicity.

Single chain variable fragments ( scFv) are connected to the ig free dot net domain of the heavy and light chain via a short linker peptide.

ig free dot net

The linker is rich in glycine, which gives it more flexibility, and serine/threonine, which gives it specificity. Two different scFv fragments can be connected together, via a hinge region, to the constant domain of the heavy chain or the constant domain of the light chain. [57] This gives the antibody bispecificity, allowing for the binding specificities of two different antigens. [58] The "knobs-into-holes" format enhances heterodimer formation but doesn't suppress homodimer formation.

To further improve the function of heterodimeric antibodies, many scientists are looking towards artificial constructs. Artificial antibodies are largely diverse protein motifs that use the functional strategy of the antibody molecule, but aren't limited by the loop and framework structural constraints of the natural antibody.

[59] Being able to control the combinational design of the sequence and three-dimensional space could transcend the natural design and allow for the attachment of different combinations of drugs to the arms. Heterodimeric antibodies have a greater range in shapes they can take and the drugs that are attached to the arms don't have to be the same on each arm, allowing for different combinations of drugs to be used in cancer treatment.

Pharmaceuticals are able to produce highly functional bispecific, and even multispecific, antibodies. The degree to which they can function is impressive given that such a change of shape from the ig free dot net form should lead to decreased functionality.

History [ edit ] See also: History of immunology The first use of the term "antibody" occurred in a text by Paul Ehrlich. The term Antikörper (the German word for antibody) appears in the conclusion of his article "Experimental Studies on Immunity", published in October 1891, which states that, "if two substances give rise to two different Antikörper, then they themselves must be different". [60] However, the term was not accepted immediately and several other terms for antibody were proposed; these included Immunkörper, Amboceptor, Zwischenkörper, substance sensibilisatrice, copula, Desmon, philocytase, fixateur, and Immunisin.

ig free dot net

{INSERTKEYS} [60] The word antibody has formal analogy to the word antitoxin and a similar concept to Immunkörper ( immune body in English). [60] As such, the original construction of the word contains a logical flaw; the antitoxin is something directed against a toxin, while the antibody is a body directed against something.

[60] Angel of the West (2008) by Julian Voss-Andreae is a sculpture based on the antibody structure published by E. Padlan. [61] Created for the Florida campus of the Scripps Research Institute, [62] the antibody is placed into a ring referencing Leonardo da Vinci's Vitruvian Man thus highlighting the similarity of the antibody and the human body.

[63] The study of antibodies began in 1890 when Emil von Behring and Kitasato Shibasaburō described antibody activity against diphtheria and tetanus toxins. Von Behring and Kitasato put forward the theory of humoral immunity, proposing that a mediator in serum could react with a foreign antigen. [64] [65] His idea prompted Paul Ehrlich to propose the side-chain theory for antibody and antigen interaction in 1897, when he hypothesized that receptors (described as "side-chains") on the surface of cells could bind specifically to toxins – in a "lock-and-key" interaction – and that this binding reaction is the trigger for the production of antibodies.

[66] Other researchers believed that antibodies existed freely in the blood and, in 1904, Almroth Wright suggested that soluble antibodies coated bacteria to label them for phagocytosis and killing; a process that he named opsoninization. [67] Michael Heidelberger In the 1920s, Michael Heidelberger and Oswald Avery observed that antigens could be precipitated by antibodies and went on to show that antibodies are made of protein.

[68] The biochemical properties of antigen-antibody-binding interactions were examined in more detail in the late 1930s by John Marrack.


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{INSERTKEYS} [69] The next major advance was in the 1940s, when Linus Pauling confirmed the lock-and-key theory proposed by Ehrlich by showing that the interactions between antibodies and antigens depend more on their shape than their chemical composition. [70] In 1948, Astrid Fagraeus discovered that B cells, in the form of plasma cells, were responsible for generating antibodies.

[71] Further work concentrated on characterizing the structures of the antibody proteins. A major advance in these structural studies was the discovery in the early 1960s by Gerald Edelman and Joseph Gally of the antibody light chain, [72] and their realization that this protein is the same as the Bence-Jones protein described in 1845 by Henry Bence Jones. [73] Edelman went on to discover that antibodies are composed of disulfide bond-linked heavy and light chains.

Around the same time, antibody-binding (Fab) and antibody tail (Fc) regions of IgG were characterized by Rodney Porter. [74] Together, these scientists deduced the structure and complete amino acid sequence of IgG, a feat for which they were jointly awarded the 1972 Nobel Prize in Physiology or Medicine.

[74] The Fv fragment was prepared and characterized by David Givol. [75] While most of these early studies focused on IgM and IgG, other immunoglobulin isotypes were identified in the 1960s: Thomas Tomasi discovered secretory antibody ( IgA); [76] David S.

Rowe and John L. Fahey discovered IgD; [77] and Kimishige Ishizaka and Teruko Ishizaka discovered IgE and showed it was a class of antibodies involved in allergic reactions. [78] In a landmark series of experiments beginning in 1976, Susumu Tonegawa showed that genetic material can rearrange itself to form the vast array of available antibodies. [79] Medical applications [ edit ] Disease diagnosis [ edit ] Detection of particular antibodies is a very common form of medical diagnostics, and applications such as serology depend on these methods.

[80] For example, in biochemical assays for disease diagnosis, [81] a titer of antibodies directed against Epstein-Barr virus or Lyme disease is estimated from the blood. If those antibodies are not present, either the person is not infected or the infection occurred a very long time ago, and the B cells generating these specific antibodies have naturally decayed.

In clinical immunology, levels of individual classes of immunoglobulins are measured by nephelometry (or turbidimetry) to characterize the antibody profile of patient. [82] Elevations in different classes of immunoglobulins are sometimes useful in determining the cause of liver damage in patients for whom the diagnosis is unclear.

[1] For example, elevated IgA indicates alcoholic cirrhosis, elevated IgM indicates viral hepatitis and primary biliary cirrhosis, while IgG is elevated in viral hepatitis, autoimmune hepatitis and cirrhosis. Autoimmune disorders can often be traced to antibodies that bind the body's own epitopes; many can be detected through blood tests.

Antibodies directed against red blood cell surface antigens in immune mediated hemolytic anemia are detected with the Coombs test.

[83] The Coombs test is also used for antibody screening in blood transfusion preparation and also for antibody screening in antenatal women. [83] Practically, several immunodiagnostic methods based on detection of complex antigen-antibody are used to diagnose infectious diseases, for example ELISA, immunofluorescence, Western blot, immunodiffusion, immunoelectrophoresis, and magnetic immunoassay. Antibodies raised against human chorionic gonadotropin are used in over the counter pregnancy tests.

New dioxaborolane chemistry enables radioactive fluoride ( 18F) labeling of antibodies, which allows for positron emission tomography (PET) imaging of cancer. [84] Disease therapy [ edit ] Targeted monoclonal antibody therapy is employed to treat diseases such as rheumatoid arthritis, [85] multiple sclerosis, [86] psoriasis, [87] and many forms of cancer including non-Hodgkin's lymphoma, [88] colorectal cancer, head and neck cancer and breast cancer.

[89] Some immune deficiencies, such as X-linked agammaglobulinemia and hypogammaglobulinemia, result in partial or complete lack of antibodies. [90] These diseases are often treated by inducing a short-term form of immunity called passive immunity.

Passive immunity is achieved through the transfer of ready-made antibodies in the form of human or animal serum, pooled immunoglobulin or monoclonal antibodies, into the affected individual. [91] Prenatal therapy [ edit ] Rh factor, also known as Rh D antigen, is an antigen found on red blood cells; individuals that are Rh-positive (Rh+) have this antigen on their red blood cells and individuals that are Rh-negative (Rh–) do not.

During normal childbirth, delivery trauma or complications during pregnancy, blood from a fetus can enter the mother's system. In the case of an Rh-incompatible mother and child, consequential blood mixing may sensitize an Rh- mother to the Rh antigen on the blood cells of the Rh+ child, putting the remainder of the pregnancy, and any subsequent pregnancies, at risk for hemolytic disease of the newborn.

[92] Rho(D) immune globulin antibodies are specific for human RhD antigen. [93] Anti-RhD antibodies are administered as part of a prenatal treatment regimen to prevent sensitization that may occur when a Rh-negative mother has a Rh-positive fetus.

Treatment of a mother with Anti-RhD antibodies prior to and immediately after trauma and delivery destroys Rh antigen in the mother's system from the fetus. It is important to note that this occurs before the antigen can stimulate maternal B cells to "remember" Rh antigen by generating memory B cells. Therefore, her humoral immune system will not make anti-Rh antibodies, and will not attack the Rh antigens of the current or subsequent babies.

Rho(D) Immune Globulin treatment prevents sensitization that can lead to Rh disease, but does not prevent or treat the underlying disease itself.

[93] Research applications [ edit ] Immunofluorescence image of the eukaryotic cytoskeleton. Microtubules as shown in green, are marked by an antibody conjugated to a green fluorescing molecule, FITC.

Specific antibodies are produced by injecting an antigen into a mammal, such as a mouse, rat, rabbit, goat, sheep, or horse for large quantities of antibody. Blood isolated from these animals contains polyclonal antibodies—multiple antibodies that bind to the same antigen—in the serum, which can now be called antiserum.

Antigens are also injected into chickens for generation of polyclonal antibodies in egg yolk. [94] To obtain antibody that is specific for a single epitope of an antigen, antibody-secreting lymphocytes are isolated from the animal and immortalized by fusing them with a cancer cell line.

The fused cells are called hybridomas, and will continually grow and secrete antibody in culture. Single hybridoma cells are isolated by dilution cloning to generate cell clones that all produce the same antibody; these antibodies are called monoclonal antibodies.

[95] Polyclonal and monoclonal antibodies are often purified using Protein A/G or antigen-affinity chromatography. [96] In research, purified antibodies are used in many applications.

Antibodies for research applications can be found directly from antibody suppliers, or through use of a specialist search engine. Research antibodies are most commonly used to identify and locate intracellular and extracellular proteins. Antibodies are used in flow cytometry to differentiate cell types by the proteins they express; different types of cells express different combinations of cluster of differentiation molecules on their surface, and produce different intracellular and secretable proteins.

[97] They are also used in immunoprecipitation to separate proteins and anything bound to them (co-immunoprecipitation) from other molecules in a cell lysate, [98] in Western blot analyses to identify proteins separated by electrophoresis, [99] and in immunohistochemistry or immunofluorescence to examine protein expression in tissue sections or to locate proteins within cells with the assistance of a microscope.

[97] [100] Proteins can also be detected and quantified with antibodies, using ELISA and ELISpot techniques. [101] [102] Antibodies used in research are some of the most powerful, yet most problematic reagents with a tremendous number of factors that must be controlled in any experiment including cross reactivity, or the antibody recognizing multiple epitopes and affinity, which can vary widely depending on experimental conditions such as pH, solvent, state of tissue etc.

Multiple attempts have been made to improve both the way that researchers validate antibodies [103] [104] and ways in which they report on antibodies. Researchers using antibodies in their work need to record them correctly in order to allow their research to be reproducible (and therefore tested, and qualified by other researchers).

Less than half of research antibodies referenced in academic papers can be easily identified. [105] Papers published in F1000 in 2014 and 2015 provide researchers with a guide for reporting research antibody use. [106] [107] The RRID paper, is co-published in 4 journals that implemented the RRIDs Standard for research resource citation, which draws data from the antibodyregistry.org as the source of antibody identifiers [108] (see also group at Force11 [109]).

Regulations [ edit ] Production and testing [ edit ] Traditionally, most antibodies are produced by hybridoma cell lines through immortalization of antibody-producing cells by chemically-induced fusion with myeloma cells. In some cases, additional fusions with other lines have created " triomas" and " quadromas". The manufacturing process should be appropriately described and validated. Validation studies should at least include: • The demonstration that the process is able to produce in good quality (the process should be validated) • The efficiency of the antibody purification (all impurities and virus must be eliminated) • The characterization of purified antibody ( physicochemical characterization, immunological properties, biological activities, contaminants, ...) • Determination of the virus clearance studies Before clinical trials [ edit ] • Product safety testing: Sterility ( bacteria and fungi), in vitro and in vivo testing for adventitious viruses, murine retrovirus testing..., product safety data needed before the initiation of feasibility trials in serious or immediately life-threatening conditions, it serves to evaluate dangerous potential of the product.

• Feasibility testing: These are pilot studies whose objectives include, among others, early characterization of safety and initial proof of concept in a small specific patient population (in vitro or in vivo testing). Preclinical studies [ edit ] • Testing cross-reactivity of antibody: to highlight unwanted interactions (toxicity) of antibodies with previously characterized tissues.

This study can be performed in vitro (reactivity of the antibody or immunoconjugate should be determined with a quick-frozen adult tissues) or in vivo (with appropriates animal models). • Preclinical pharmacology and toxicity testing: preclinical safety testing of antibody is designed to identify possible toxicity in humans, to estimate the likelihood and severity of potential adverse events in humans, and to identify a safe starting dose and dose escalation, when possible.

• Animal toxicity studies: Acute toxicity testing, repeat-dose toxicity testing, long-term toxicity testing • Pharmacokinetics and pharmacodynamics testing: Use for determinate clinical dosages, antibody activities, evaluation of the potential clinical effects Structure prediction and computational antibody design [ edit ] The importance of antibodies in health care and the biotechnology industry demands knowledge of their structures at high resolution.

This information is used for protein engineering, modifying the antigen binding affinity, and identifying an epitope, of a given antibody. X-ray crystallography is one commonly used method for determining antibody structures.

However, crystallizing an antibody is often laborious and time-consuming. Computational approaches provide a cheaper and faster alternative to crystallography, but their results are more equivocal, since they do not produce empirical structures.

Online web servers such as Web Antibody Modeling (WAM) [110] and Prediction of Immunoglobulin Structure (PIGS) [111] enables computational modeling of antibody variable regions. Rosetta Antibody is a novel antibody F V region structure prediction server, which incorporates sophisticated techniques to minimize CDR loops and optimize the relative orientation of the light and heavy chains, as well as homology models that predict successful docking of antibodies with their unique antigen.

[112] However, describing an antibody's binding site using only one single static structure limits the understanding and characterization of the antibody's function and properties. To improve antibody structure prediction and to take the strongly correlated CDR loop and interface movements into account, antibody paratopes should be described as interconverting states in solution with varying probabilities. [17] The ability to describe the antibody through binding affinity to the antigen is supplemented by information on antibody structure and amino acid sequences for the purpose of patent claims.

[113] Several methods have been presented for computational design of antibodies based on the structural bioinformatics studies of antibody CDRs. [114] [115] [116] There are a variety of methods used to sequence an antibody including Edman degradation, cDNA, etc.; albeit one of the most common modern uses for peptide/protein identification is liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS).

[117] High volume antibody sequencing methods require computational approaches for the data analysis, including de novo sequencing directly from tandem mass spectra [118] and database search methods that use existing protein sequence databases. [119] [120] Many versions of shotgun protein sequencing are able to increase the coverage by utilizing CID/HCD/ETD [121] fragmentation methods and other techniques, and they have achieved substantial progress in attempt to fully sequence proteins, especially antibodies.

Other methods have assumed the existence of similar proteins, [122] a known genome sequence, [123] or combined top-down and bottom up approaches.

[124] Current technologies have the ability to assemble protein sequences with high accuracy by integrating de novo sequencing peptides, intensity, and positional confidence scores from database and homology searches. [125] Antibody mimetic [ edit ] Antibody mimetics are organic compounds, like antibodies, that can specifically bind antigens. {/INSERTKEYS}

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They consist of artificial peptides or proteins, or aptamer-based nucleic acid molecules with ig free dot net molar mass of about 3 to 20 kDa. Antibody fragments, such as Fab and nanobodies are not considered as antibody mimetics. Common advantages over antibodies are better solubility, tissue penetration, stability towards heat and enzymes, and comparatively low production costs.

Antibody mimetics have being developed and commercialized as research, diagnostic and therapeutic agents. [126] Optimer ligands [ edit ] Optimer ligands are a novel class of antibody mimetics. [127] These nucleic acid based affinity ligands are developed in vitro to generate specific and sensitive affinity ligands that are being applied across therapeutics, [128] [129] drug delivery, [130] [131] [132] bioprocessing, [133] [134] diagnostics, [135] [136] [137] [138] [139] [140] [141] and basic research.

[140] Binding antibody unit [ edit ] BAU (binding antibody unit, often as BAU/mL) is a measurement unit defined by the WHO for the comparison of assays detecting the same class of immunoglobulins with the same specificity. [142] [143] [144] See also [ edit ] • Affimer • Anti-mitochondrial antibodies • Anti-nuclear antibodies • Antibody mimetic • Aptamer • Colostrum • ELISA • Humoral immunity • Immunology • Immunosuppressive drug • Intravenous immunoglobulin (IVIg) • Magnetic immunoassay • Microantibody • Monoclonal antibody • Neutralizing antibody • Optimer Ligand • Secondary antibodies • Single-domain antibody • Slope spectroscopy • Synthetic antibody • Western blot normalization References [ edit ] • ^ a b c Rhoades RA, Pflanzer RG (2002).

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I did not realized the difficulty of writing the parting notes at the end of this blog’s journey (also see goodbye).

I’ve put off writing for days and have instead worked on a stone pathway in my garden. It’s still unfinished but I’ve exhausted myself enough to sit down and write something today. It felt as if after 5,110 days of running this blog, I’d ran out of things to say. Or perhaps it’s just that some things have changed and yet remained the same and that I’ve laughed myself silly for living in a simulation🤣! In any case, I will try to write down a few parting thoughts.

Via Pexels Social Media When we started this blog over a decade ago, Foggy Bottom’s usage of social media was just getting its sea legs. Blogging was a source of excitement and anxiety (see Foreign Service Blogging: Tigers Have Teeth, Rather Sharp … Rawr!!!).

These days, we see folks, even self-identified high-ranking Foggy Bottom denizens, writing on their personal Twitter profile that their “tweets = personal views”. Do you remember in the old days (and in FSGB cases), being told that you are on duty 24/7? That is, you are on duty 24/7 until the government decides that you are not. That old political counselor who told his foreign counterpart that he had no personal opinion, only an official opinion would seem like a dinosaur these days.

Last year, two FS employees made the big news for social media posts, and one for r eported participation in the Jan. 6 attack (remember – No Insurrectionists in America’s Diplomatic Service. How times have changed!

Twitter remains a dangerous sinkhole, official or otherwise. A tweet is immediate, and a retweets can travel quite a distance rather quickly. For my readers who are in the FS, it still pays to be prudent what you tweet or retweet in your personal capacity, especially if you are self-identified as a U.S.

diplomat. Foreign Service Spouses In 2009, I wrote Diplomatic Spouse Employment: A Drip in a Large Tin Roof. Ten years later, do you seriously think that the prospects for spouse employment would be a lot different?

I’ve come to the sad conclusion that the lives of most FS spouses will continue to be challenging in the years to come. And their financial future will continue to be perilous. As American families become dual-income couples, the FS families will continue to be largely one employee working. Because it is not a priority, a majority of spouses will remain unable to work while overseas, thus, limiting their ability to prepare for their own retirement.

Time is a limited resource; once you’ve spent it, you won’t ever get it back. That applies to age and retirement accounts. Don’t forget to attend the Retirement Seminar you say? What about if State starts allowing folks to take the retirement seminar upon tenure? Wouldn’t that make more sense for long term planning purposes?

Of course, spouses may only attend on “a space-available basis” as often the case with State. Drat that! Actually, it occurred to me that if more spouses have access to the retirement seminar, more employees may be forced to head for the exit.

While some agencies operating overseas have made provisions for spouses to be employed at certain jobs at US missions, it remains a hit or miss for State Department spouses. Even when State can centrally fund jobs so they do not come out of post funds, State often doesn’t. One can blame Congress for consistently under funding diplomacy, but one can also recognize that jobs for spouses isn’t on any Ig free dot net of State’s priority list, not even for retention purposes.

Does State even know how many employees resign due to the inability of spouses to keep a career? Data not collected, hey? At some point in the future, it may be that only the independently wealthy can again afford to go overseas to represent our country.

Accountability In early 2014, State/OIG confirmed to this blog that the practice of preparing Inspector’s Evaluation Reports (IERs) ended in April 2013. Ambassador Pancho Huddle, who previously served as U.S. Ambassador to Tajikistan and spent five years as a senior OIG inspector at the State Department, told us then: “When OIG dumped their IERs, they dumped their ability to make a real difference.” And I totally agree.

I remain convinced that it was wrong to end that practice. All teeth, but no bite have repercussions. Recently, after 11 years, State/OIG returned to US Embassy Luxembourg. The 2011 report detailed poor management issues and stated that two DCMs, two section chiefs, and other employees either curtailed or volunteered for service in Kabul or Baghdad.

That political ambassador resigned. Once that report was released, it generated a media feeding frenzy. The 2022 report did not indicate much of an improvement.

Post’s authorized staff included 32 U.S. direct- hire employees. A staff turn over of 42 percent over a 2 ½- year period under another political ambassador did not prompt any noticeable reaction from the Department or the media. Of course, this time around, the OIG did not show up in Luxembourg until three months after the well-connected political ambassador had departed!

But seriously! The DGHR and Undersecretary for Management must know about the curtailments of almost half the mission. No one thought to ask what’s going on when post got to 25% staff curtailments? Or it didn’t matter? Or was it simply acceptable losses to keep an appointee in place? Moving people and household cost money. But who cares, right? It’s only taxpayers money. In the last administration in particular, accountability was just a long, strange word to be admired.

In several documented cases of bosses behaving badly, and many more not documented in public reports, nothing really happened. Remember IO?

Protocol? Or when top State Department officials commented on a leaked IG report and attacked the OIG? Or when the OIG was fired under cover of darkness?

I must add that the current administration has now nominated a political appointee whose performance was blasted in an OIG report during a prior tenure. I hate to say this but it is likely that political connections and consideration will win the day and this nominee will get confirmed by the U.S. Senate no matter what the OIG report said in 2015.

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While, I’m thinking about accountability, perhaps Secretary Blinken busy as he is these days, should task one of his top lieutenants to see what should be done about the reported toxic workplace at the Office of Civil Rights (S/OCR). The office that leads global training on the prevention of workplace harassment and is tasked with investigating sexual harassment appears to be a problem in itself. The OIG reportedly wasn’t interested in looking into various allegations in that office and did not respond to our inquiry.

We’re hoping Congress can get the GAO to take a look. DCMs as CDAs In the old days, when the ambassador left office, the deputy chief of mission (DCM) routinely stepped in as charge d’affairs (CDA) (the accredited diplomat who serves as the embassy’s chief of mission ig free dot net the absence of the ambassador or until a new ambassador arrives).

This is how DCMs got their experience in leading the mission; it also allowed section chiefs to be acting DCMs and afford them the experience of running the embassy. In the last few years we’ve observed a change in this routine practice. In some cases, the State Department recalls retired FSOs to work as CDAs; in other cases, Foggy Bottom officials are sent out to manage the embassy until a nominee is confirmed by the U.S. Senate. What signal does this send to the active service members?

We are aware of a few cases when DCMs who stepped in as CDAs were not functioning as expected (micromanagement, staff threatening curtailments, etc).

It may be that in those case, Foggy Bottom had to send somebody to help steer the ship, but if DCMs are no longer afforded the traditional practice of becoming CDAs, when should they learn how to become COMs? Assaults and Harassment Readers following this blog are aware of the series of blogposts we wrote about sexual harassment and assaults in the Foreign Service. Those posts were some of the most difficult stories I had to write. Probably half the stories I heard did not make it to the blog because the survivors wanted me to hear their stories but did not want to share them publicly.

In the fall of 2016, we blogged that the Department’s Sexual Assault Reporting Procedure Appears to Be a Black Hole of Grief. In November of that year, the Department finally directed a task force to create a new section in the Foreign Affairs Manual for sexual assault (see U/S For Management Directs Task Force to Create New Sexual Assault FAM Guidance).

In 2017, the Department released a new section of the FAM addressing sexual assault reporting procedures (see @StateDept Releases New Sexual Assault Guidance For COM Personnel & Facilities Outside the United States).

3 FAM 1700 is far from perfect but sexual assault reporting wasn’t even in the FAM previously, so this was a start. If this blog played a role in lighting a fire under State to get that done, I am satisfied. The Department sent us a note at that time “to make absolutely sure” that we have seen it and gave us an “officially provided” copy of the new section.

In 2020, State/OIG r eleased the long-awaited report on the Department’s handling of sexual harassment reports. It was distressing to read. Both the investigations conducted vs the reported complaints and the underreporting are striking.

Of the 24 cases where misconduct allegations including sexual assaults were substantiated, we have no idea how many perpetrators were criminally charged. While I’m writing about this, a quick reminder that every COM facility with an assigned FS Medical Specialist should have at least three Sexual Assault Evidence Collection Kit (SAEC Kit) per 3 FAM 1700. Make sure your post have them.

Funny Bone Gone Our 14 years of blogging about the State Department and the Foreign Service included poking fun at the Foggiest Bottom here, here, here here, and here. But only once did I received an official take down request (see Aww — @StateDept Sends Official Take Down Request For April Ig free dot net Day Cable). In April 1, 2017, I wrote, Inside @StateDept: Leaked Cable Provides Guidance For ‘America First’ Cost Savings Initiatives.

Apparently, it wasn’t funny at all for the 7th Floor people. Poor things, they could not find their tickle bones.

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Now, poor me, I’ve misplaced my funny bone after the back to back performances of T-Rex and the Mikey Po. You, too? And finally … When I started blogging in 2008, some readers told me they read this blog in secret; that no one in their offices would admit to reading the blog.

Not sure what was the penalty if caught reading the blog then. Years later, I would get occasional notes from individuals telling me that they had informed this office or that office that they have reported their complaints to this blog. Goodness me! I’ve almost always pass up on those stories because there are processes in place that exist for a reason, and frankly, I did not appreciate being used as a “We told the witch, watch out!” warning. How times changed!

I hope our readers join us in sending thanks to our diplomatic employees and their families. Thank you for your dedication to our country and for your willingness to serve in often difficult and dangerous places. Thank you, also, to the foreign service national employees whose support is essential to our overseas operations.

I understand and appreciate the hardships you face and the sacrifices you all make. I am sad to leave but you have my deep respect and admiration. ### By the time you’re reading this, it would be 657 days since the State Department had a Senate-confirmed Inspector General. Despite the beating that office suffered during the previous administration, the current administration does not seem to be in any great hurry to nominate an Inspector General for the State Department. IG Quick Facts: IG Independence - Congress created OIGs to strike a workable balance for IGs and agency principals.

This balance is accomplished through a number of provisions of the IG Act. The IG Act specifically prohibits agency management officials from supervising the IG. This organizational independence helps limit the potential for conflicts of interest when an audit or investigative function is placed under the authority of the official whose programs are being scrutinized.

The IG Act insulates IGs against reprisal and promotes independent and objective reporting. Additionally, the IG Act promotes independence through individual reporting of OIG budgets. For example, Section 6(g) requires OIG’s requested budget to be separately identified within the Department of State’s budget. Section 6(g)(3) authorizes OIG to comment to Congress on the sufficiency of its budget if the amount proposed in the President’s budget would substantially inhibit the IG from performing the duties of the office.

Additionally, the Department of State Authorities Act, Fiscal Year 2017, requires annual certification by the Secretary that the Department has ensured the integrity and independence of OIG’s network, information systems, and files. IG Access to Agency Principal - The IG is required to have direct and prompt access to the agency principal when necessary to perform his or her functions and responsibilities. This helps ensure that the agency principal is directly and promptly alerted to serious problems and abuses within the ig free dot net.

Conversely, the Department of State is required to submit to OIG—within 5 business days of becoming aware of the allegation—a report of any allegation of (1) waste, fraud, or abuse in a Department program or operation; (2) criminal or serious misconduct on the part of a Department employee at the FS – 1, GS-15, or GM-15 level or higher; (3) criminal misconduct on the part of a Department employee at any level; and (4) serious, noncriminal misconduct on the part of any Department employee who is authorized to carry a weapon, make arrests, or conduct searches.

IG Reporting Obligations - The IG Act creates a dual-reporting obligation for IGs—to keep both Congress ig free dot net the agency principal fully and currently informed about deficiencies ig free dot net agency programs and operations.

Unfortunately, the Quick Facts does not include what can be done when the agency principal gets the IG fired for no reason beyond the office conducting ig free dot net investigations that made the IG “a bad actor” in the eyes of the principal and his cronies. The last time there was a lengthy vacancy at the IG, it was for almost 2,000 days or 5.4 years (see After 1,989 Day-Vacancy — President Obama Nominates Steve Linick as State Dept Inspector General).

Harold W. Geisel served as Acting IG from 2008-2013. Steve Linick served from 2013-2020. After Linick’s firing, Stephen Akard served as Acting IG for three months, Diana Shaw was Acting IG for a month, and Matthew Klimow served as Acting IG from August-December 2020.

Diana Shaw once again became Acting IG for the State Department in December 2020 and continues to serve in that role to-date. Congressional members made lots of noises, of course, after the Linick firing.

They even conducted hearings. Which did not amount to anything really. Nothing happened besides a bad news cycle for Mikey Po so what could possibly dissuade any agency principal from doing exactly the same thing? Defense (2,245 days) and OPM (2,204 days) currently have longer IG vacancies than State but the WH has previously announced the nominees for those agencies and they are currently awaiting confirmation. Whereas State (and Treasury) have been forgotten by the time lords.

We hope this isn’t a purposeful omission that could last the entire Blinken tenure. It also occurred to us that one can ig free dot net all the messiness of firing an IG by not appointing one. ### On March 1, the State Department issued new guidance on land border crossings for U.S. citizens departing Ukraine. U.S. citizens wishing to depart Ukraine by land have several options, listed below. We understand that most border crossings into Poland and all main crossing points into Moldova are severely backed up and some are experiencing extremely long wait times (well over 30 hours in some cases).

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We recommend that, if possible, U.S. citizens consider redirecting to border crossings ig free dot net Hungary, Romania, and Slovakia, which are currently experiencing lower wait times to cross. Note that conditions at each border can change very quickly and wait times can increase at any time without warning. Be prepared to wait for many hours to cross: • • Have extra batteries and power banks for your mobile phones.

• Bring enough food and water for at least two days. • Stock up on diapers and baby food, if applicable. • Bring blankets, sleeping bags, warm clothes. • Ensure enough pet food if you are with your pet. • Bring hard copies of important documents (birth certificates, passports [even if expired], any other identification) and don’t rely on cell phones and computer batteries. • Book accommodations prior to arrival, as many hotels near the borders are already booked.

Local authorities in Romania, Poland, and Moldova have reception centers immediately beyond most border crossings, where you can find food, temporary lodging, clothes, and transportation to the next bigger town. Specific info on entering neighboring countries from Ukraine • • Poland • Romania • Hungary • Slovakia • Moldova • Belarus (do not travel) • Russia (do not travel) Read more here.

US EMBASSY POLAND Byłem dziś razem z @Trzaskowski_ w centrum dla uciekających przed wojną w Ukrainie, na dworcu Warszawa Wschodnia. Imponujące jest zaangażowanie i dobra wola Polaków.

Cieszę się, że mogą pomagać sami czując się bezpiecznie. pic.twitter.com/jiQZVsMBRF — Ambasador Mark Brzezinski (@USAmbPoland) March 2, 2022 U.S.

citizens departing Ukraine: Poland-Ukraine border crossings remain open, although long waits are reported. Poland has suspended COVID-19 related entry and testing requirements. Have identity, travel documents ready at the time of crossing. More info: https://t.co/PzjBLR8NZE https://t.co/9v9wTDgCJW — US Embassy Warsaw (@USEmbassyWarsaw) March 2, 2022 US EMBASSY ROMANIA 🇺🇸 Embassy staff visited the Siret Border Crossing Point today.

They met with officials, civil society, & volunteers all helping refugees flee the 🇷🇺 invasion in 🇺🇦. Romanian government and private compassion & care is profound & it is needed. #compassion #StandWithUkraine pic.twitter.com/ObadELpUuA — US Embassy Bucharest (@AmbasadaSUA) March 2, 2022 US EMBASSY HUNGARY CDA Marc Dillard visited the Zahony border crossing and the Embassy border support team.

We will continue to provide support and assistance to the people of 🇺🇦 in response to this unprovoked and unjustified attack by Russia. #UnitedWithUkraine pic.twitter.com/CnoaIw9fTI — US Embassy Budapest (@usembbudapest) March 1, 2022 US EMBASSY SLOVAKIA Ukraine has shown incredible strength and determination as they face this ig free dot net and unjustified attack by Russia.

We stand together for the women, children and men of #Ukraine as they fight to defend themselves. We All Stand Together #UnitedWithUkraine #StrongerTogether pic.twitter.com/0rT3xPS3Vr — USembassySK (@USEmbassySK) March 2, 2022 ### U.S.

EMBASSY BELARUS 3/4 Belarusian authorities have taken a series of hostile actions to limit @USEmbBy ability to work with the Belarusian people and advance America’s interests, including forced staff reductions, closure of @USAIDBelarus & US cultural center in Minsk.

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— Julie Fisher (@USAmbBelarus) February 28, 2022 U.S. EMBASSY UKRAINE State Ukraine Task Force should include a dedicated effort to provide direct support to LES (locally employed staff). Unlike Afghanistan, Ukraine is surrounded by several friendly neighboring countries all of which have US Embassies. The TF needs a senior rep to coordinate exits. — Jenna Ben-Yehuda (@jenna_dc) February 26, 2022 Exclusive: Ukrainians who worked at US embassy plead for help, fear being left behind “Before, we were told that Ukraine is not Afghanistan,” they wrote to State Dept.

“We need your help now. This is not a time to wait and research. This is time to act“ https://t.co/kczh4kl3Ou — Robbie Gramer (@RobbieGramer) February 25, 2022 NEW: Nearly 400 foreign service officers and other staff criticized the State Department’s “lack of responsiveness” to requests for help from their Ukrainian colleagues in an email to leadership.

“Our Ukrainian colleagues deserve better." https://t.co/Amg6rnpDsP — Vivian Salama (@vmsalama) February 25, 2022 U.S. EMBASSY YEMEN Statement from the U.S. Embassy to Yemen Regarding the Ongoing Detention and Harassment of Our Local Staff. pic.twitter.com/lWdtMHGHjE — US Embassy to Yemen السفارة الأمريكية في اليمن (@USEmbassyYemen) February 25, 2022 ### On February 28, 2022, the State Department also announced the US Embassy Moscow is now under an “authorized departure” order for non-emergency staff and USG family members.

The U.S. Department of State has suspended operations at our Embassy in Minsk, Belarus and authorized the voluntary departure (“authorized departure”) of non-emergency employees and family members at our Embassy in Moscow, Russia.

We took these steps due to security and safety issues stemming from the unprovoked and unjustified attack by Russian military forces in Ukraine. The Department of State continually adjusts its posture at embassies and consulates throughout the world in line with its mission, the local security environment, and the health situation.

We ultimately have no higher priority than the safety and security of U.S. citizens, and that includes our U.S. government personnel and their dependents serving around the world. Also on February 28, the State Department issued an updated Level 4-Do Not Travel Advisory for Russia citing the Russian military forces attack in Ukraine, the potential harassment of American citizens, and limited flights out of the country among other things, and urge their departure from Russia while commercial flights ig free dot net still available.

Do not travel to Russia due to the unprovoked and unjustified attack by Russian military forces in Ukraine, the potential for harassment against U.S. citizens by Russian government security officials, the embassy’s limited ability to assist U.S.

citizens in Russia, COVID-19 and related entry restrictions, terrorism, limited flights into and out of Russia, and the arbitrary enforcement of local law. U.S. citizens should consider departing Russia immediately via commercial options still available. Due to Russia’s further invasion of Ukraine, an increasing number of airlines are cancelling flights into and out of Russia, and numerous countries have closed their airspace to Russian airlines.

In addition, air space around southern Russia is restricted and a number of airports in the area have closed. U.S. citizens located in or considering travel to the districts of ig free dot net Russian Federation immediately bordering Ukraine should be aware that the situation along the border is dangerous and unpredictable.

Given the ongoing armed conflict, U.S. citizens are strongly advised against traveling by land from Russia to Ukraine. In addition, there is the potential throughout Russia of harassment towards foreigners, including through regulations targeted specifically against foreigners. Given the ongoing armed conflict and the potentially significant impact on international travel options, U.S. citizens should consider departing Russia immediately via commercial options still available.

The Advisory notes that the embassy’s ability to provide routine or emergency assistance to Americans is severely limited, as well as the voluntary evacuation of non-emergency personnel and USG family members from the country: The U.S.

government’s ability to provide routine or emergency services to U.S. citizens in Russia is severely limited, particularly in areas far from the U.S. Embassy in Moscow due to Russian government limitations on U.S. staffing and travel, and the ongoing suspensions of operations, including consular services, at U.S. consulates. On February 28, the Department of State authorized the voluntary departure of eligible family members and non-emergency personnel from U.S.

Embassy Moscow. Also on February 28, @USUN Spokesperson Olivia Dalton issued a statement on the expulsion of 12 Russians reportedly intelligence operatives at the Russian Mission at the United Nations for “engaging in espionage activities that are adverse to our national security:” The United States has informed the United Nations and the Russian Permanent Mission to the United Nations that we are beginning the process of expelling twelve intelligence operatives from the Russian Mission who have abused their privileges of residency in the United States by engaging in espionage activities that are adverse to our national security.

We are taking this action in accordance with the UN Headquarters Agreement. This action has been in development for several months. The U.S. has expelled 12 Russian diplomats who ‘abused their privileges of residency in the United States by engaging in espionage activities that are adverse to [U.S.] national security’ pic.twitter.com/4y1EwWD8VY — NowThis (@nowthisnews) February 28, 2022 U.S.

announces 12 Russian diplomats at #UN as persona non grata, says #Russia's UN representative Nebenzya pic.twitter.com/KJTNnQEmnJ — NEXTA (@nexta_tv) February 28, 2022 On February 28, 2022, the State Department announced the suspension of operations at the US Embassy in Minsk, Belarus: The U.S. Department of State has suspended operations at our Embassy in Minsk, Belarus and authorized the voluntary departure (“authorized departure”) of non-emergency employees and family members at our Embassy in Moscow, Russia.

We took these steps due to security and safety issues stemming from the unprovoked and unjustified attack by Russian military forces in Ukraine. The Department of State continually adjusts its posture at embassies and consulates throughout the world in line with its mission, the local security environment, and the health situation.

We ultimately have no higher priority than the safety and security of U.S. citizens, and that includes our U.S. government personnel and their dependents serving around the world. The embassy in Minsk has suspended operations.

For U.S. citizens in Belarus who need assistance, please see this advisory for useful contact information: https://t.co/rNm0pOTb1P https://t.co/tzysWLAy8o — U.S. Embassy Minsk (@USEmbBy) February 28, 2022 1/4 The United States of America has suspended operations of our embassy in Minsk. All American staff have departed Belarus. pic.twitter.com/Og8iynLdi6 — Julie Fisher (@USAmbBelarus) February 28, 2022 New: U.S. closes its embassy in Belarus as Lukashenko backs Putin's war.

“Belarus’ complicity in Russia’s war against Ukraine has shown the regime’s loss of sovereign decision-making” U.S. envoy to Belarus says https://t.co/t025kHDBpM — Robbie Gramer (@RobbieGramer) February 28, 2022 ### The expulsion comes as tensions between the United States and Russia hit a post-Cold War high over Ukraine. But a U.S. official said move was unrelated to the unfolding invasion, but is instead part of a long-running dispute over embassy staffing.

https://t.co/8uMkkb96l3 — Radio Free Europe/Radio Liberty (@RFERL) February 24, 2022 WASHINGTON (AP) — The United States has expelled Russia’s second-ranking diplomat in Washington in retaliation for the Russian expulsion of the No.

2 U.S. diplomat in Moscow earlier this month, a senior State Department official said Thursday. https://t.co/neY1E2c7Jq — Julie Pace (@JuliePace) February 24, 2022 The 2nd-highest ranking Russian diplomat is being expelled from the US in retaliation for a similar move made by Russia earlier this month, a senior State Dept.

official says. https://t.co/FGlLa18s3E — NBC News (@NBCNews) February 24, 2022 Related posts: • @StateDept Finally Confirmed Expulsion of Embassy Moscow DCM Bart Gorman Feb 18, 2022 • On Ig free dot net Diplomats’ Day, Moscow Kicks Out US Embassy DCM Feb 14, 2022 • @StateDept “continuing to evaluate the situation regarding the embassy and the staffing” in #Moscow 2021 • US Mission Russia Terminates Local Employees/Contractors Due to Moscow’s Prohibition Aug 2021 • US Mission Russia: Mass Termination of Local Staff, Severe Reduction in Consular Services Effective May 12 2021 • Russian Govt to Postpone Prohibition of US Mission Russia’s Employment of Foreign Nationals 2021 • Russia Expels U.S.

Diplomats, Closes Consulate General @USinStPete 2018 • Tit For Tat For Tit: Russia expels two US diplomats over unprovoked attack at US Embassy Moscow 2016 • US Embassy Moscow Wields Wicked Red Pen of Doom on Fake State Dept Letter 2015 "An increasing number of airlines are cancelling flights into and out of Russia, and numerous countries have closed their airspace to Russian airlines.

U.S. citizens should consider departing Ig free dot net immediately via commercial options still available." https://t.co/Y7v8sGq5uf — Diplopundit (@Diplopundit) February 28, 2022 ### Dam Square in #Amsterdam is packed with people, all in support ig free dot net #Ukraine 🇺🇦 pic.twitter.com/RmDGQDMGD9 — Thomas van Linge (@ThomasVLinge) February 27, 2022 Dozens of thousands of people supporting #Ukraine in #Prague, #CzechRepublic.

It’s probably the biggest protest about international affair in our history. Pics by: @_milan_jaros, @CT24zive, @televizninoviny pic.twitter.com/3Yvn1wW0zj — Filip Horký (@FilipHorky) February 27, 2022 This morning more than 500,000 people took to the streets of #Berlin to protest against #Russian invasion of #Ukriane. The world is united against the occupants.

#StandWithUkriane 💙💛 pic.twitter.com/F7u8XmTBa1 — NEXTA (@nexta_tv) February 27, 2022 Belarusians are chanting “Glory to Ukraine” and “Long live Belarus” from the windows of their apartments.

Today's protest continued even at night. We all feel the same feeling of unity as in 2020. pic.twitter.com/aBlZ9Kcscd — Franak Viačorka (@franakviacorka) February 27, 2022 100,000 turned out in Berlin today to protest Russia’s invasion of Ukraine and show solidarity with the Ukrainian people.

https://t.co/NvM2JtdN4W pic.twitter.com/ZkaRd75yJH — Axios (@axios) February 27, 2022 Thousands of people rallied in the Georgian capital, Tbilisi, last night, calling for an end to Russia's invasion of Ukraine.

The crowds also called for the resignation of Georgian PM Irakli Garibashvili, who said his country would not join the West in sanctioning Moscow. pic.twitter.com/GLpVbfEAew — Radio Free Europe/Radio Liberty (@RFERL) February 26, 2022 People gather in protest against Russia's attack on #Ukraine in #Tokyo #Japan as Japanese Prime Minister Fumio Kishida condemned the attack, announcing further sanctions including export controls and an asset freeze on Russia's financial institutions.

📸: Yuichi Yamazaki pic.twitter.com/mAIxzfxfoD — Getty Images News (@GettyImagesNews) February 26, 2022 Latvian crowds sing the Ukrainian national anthem in front of the Russian embassy in capital Riga https://t.co/KERmhRI90A — Naomi O'Leary (@NaomiOhReally) February 25, 2022 Ukrainian-Americans and Russian-Americans came together to protest Russia’s invasion of Ukraine outside the Russian Consulate in New York City. We spoke with the demonstrators to ig free dot net what they had to say. pic.twitter.com/zaX6dG73Xd — NBC News NOW (@NBCNewsNow) February 25, 2022 Security forces in Russia have broken up anti-war protests in several cities across the country after Russian troops launched a full-scale invasion of Ukraine.

pic.twitter.com/ZTceDscdfB — Radio Free Europe/Radio Liberty (@RFERL) February 24, 2022 About 2,500 people gathered at the Brandenburg Gate in Berlin on Thursday to protest against the Russian invasion. For the second time this week, the city had illuminated the landmark in blue and yellow to express solidarity with Ukraine.

Follow updates: https://t.co/hKLhojLcq4 pic.twitter.com/XH3ax96Q36 — The New York Times (@nytimes) February 24, 2022 . hands down, US Embassy Bahrain’s clip of NEA Acting Asst Secretary Yael Lempert huting hunting for a shawarma in Manama; the rest needs to up their game. We’re still waiting for the next representative overseas to top then Ambassador to Singapore Kirk Wagar eating durian on camera. In 2018, our diplomats at Embassy Manila did eat the most terrifying food in the world.

What are you waiting for? We have yet to see our top diplomats with boiled sheep’s head, stinky tofu … what’s that? Oh, decomposed shark carcass. Right. All in the name of food diplomacy! For more ideas, see the digustingfoodmuseum. You’re welcome! During her recent visit to #Bahrain, @StateDept_NEA's Acting Assistant Secretary Yael Lempert stopped by a local shawarma stand in her hunt to find the tastiest #shawarma in the Middle East.

pic.twitter.com/dEvP0WyYMX — U.S. Embassy Manama (@USEmbassyManama) February 17, 2022 ¡Lo mejor de México! Maravillosa comida en Amecameca con Alejandra Romero y familia en su restaurante de cuarta generación en el mercado. pic.twitter.com/ztdMiSUzUE — Embajador Ken Salazar (@USAmbMex) February 14, 2022 Beautiful weekend to explore our new home.

Today, Amy and I ate bento boxes among skyscrapers on the Mitsukoshi rooftop, checked out iconic Tsukiji fish market, and made a new friend at Shioda mameya bean shop. pic.twitter.com/3JrPI7Wa3v — ラーム・エマニュエル駐日米国大使 (@USAmbJapan) February 12, 2022 I like the energy of the new US Ambassador – just posts food pics with no further context. Practically Singaporean! https://t.co/sben0lriAP — Peter Lin #IStandWithRaeesah (@prodigalgeek) February 8, 2022 Great food at Miznon…I’ve eaten at the one in New York but in Israel it tastes even better!

What do you think Ambassador @giladerdan1? pic.twitter.com/zTuWrclXX0 — Ambassador Tom Nides (@USAmbIsrael) January 30, 2022 Ambassador-designate Flake and his wife Cheryl delight in eating kebabs in #Ankara. Flakes: “Çok lezzetli ve harika 👍👍👍” pic.twitter.com/PVLDksnbDv — U.S.

Embassy Turkey (@USEmbassyTurkey) January 8, 2022 ### Recently … • Parting Notes: Diplopundit, Ig free dot net 11, 2008-March 11, 2022 March 11, 2022 • @StateDept Inspector General Vacancy Now at 657 Days and Counting March 3, 2022 • @StateDept Issues Guidance For Ukraine Land Border Crossings March 3, 2022 • US Embassy Local Employees in the News #Ukraine #Yemen #Belarus March 1, 2022 • US Embassy Moscow Now on “Authorized Departure” For Non-Emergency Staff and USG Family Members March 1, 2022 • @StateDept Suspends Operations at the US Ig free dot net in Minsk, Belarus March 1, 2022 • In Retaliation For Gorman Expulsion, U.S.

Kicks Out No.2 Diplomat at RussianEmbassyUSA February 28, 2022 • US Embassy Moscow Issues Security Alert on Limited Flights Into and Out of Russia February 28, 2022 • Protests Around the World Against Russia’s Invasion of Ukraine February 28, 2022 • Food Diplomacy Round-Up: And the Winning Food Tweet Goes to … February 18, 2022 • The Consuls’ Files • A Daring Adventure • Dead Men Working • The Dinoia Family • Diplo Denizen • Email From the Embassy • Foreign Service Problems • Canadian Foreign Service Problems • Gifplomacy • Foreign Service Test • John Brown’s Public Diplomacy Press and Blog Review • Life After Jerusalem • Mountainrunner • The Perlman Update • Sadie Abroad • Secrecy News • The Skeptical Bureaucrat • the slow move east • Sunny in Kabul • The Text Message • Unaccompanied Baggage • Well That Was Different • We Meant Well • What did you say?

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