Allotype (immunology)

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The allotype affects the constant region (labeled CL and CH1-3 in the diagram.) AntibodyChains.svg
The allotype affects the constant region (labeled CL and CH1-3 in the diagram.)

The word allotype comes from two Greek roots, allo meaning 'other or differing from the norm' and typos meaning 'mark'. [1] In immunology, allotype is an immunoglobulin variation (in addition to isotypic variation) that can be found among antibody classes and is manifested by heterogeneity of immunoglobulins present in a single vertebrate species. The structure of immunoglobulin polypeptide chain is dictated and controlled by number of genes encoded in the germ line. [2] However, these genes, as it was discovered by serologic and chemical methods, could be highly polymorphic. This polymorphism is subsequently projected to the overall amino acid structure of antibody chains. Polymorphic epitopes can be present on immunoglobulin constant regions on both heavy and light chains, differing between individuals or ethnic groups and in some cases may pose as immunogenic determinants. [3] Exposure of individuals to a non-self allotype might elicit an anti- allotype response and became cause of problems for example in a patient after transfusion of blood [4] or in a pregnant woman. [5] However, it is important to mention that not all variations in immunoglobulin amino acid sequence pose as a determinant responsible for immune response. Some of these allotypic determinants may be present at places that are not well exposed and therefore can be hardly serologically discriminated. In other cases, variation in one isotype can be compensated by the presence of this determinant on another antibody isotype in one individual. [6] This means that divergent allotype of heavy chain of IgG antibody may be balanced by presence of this allotype on heavy chain of for example IgA antibody and therefore is called isoallotypic variant. Especially large number of polymorphisms were discovered in IgG antibody subclasses. Which were practically used in forensic medicine and in paternity testing, before replaced by modern day DNA fingerprinting. [4]

Contents

Definition and organisation of allotypes in humans

Human allotypes nomenclature was first described in alphabetical system and further systematized in numerical system, but both could be found in the literature. [7] [8] For example, allotype expressed on constant region of heavy chain on IgG are designated by Gm which stands for ‘genetic marker ‘ together with IgG subclass (IgG1 àG1m, IgG2 àG2m) and the allotype number or letter [ G1m1/ G1m (a) ]. Polymorphisms within IgA are denoted in the same way as A2m (eg. A2m1/2) and kappa light chains constant region polymorphisms as Km (eg. Km1). Despite the fact, that there are multiple known lambda chain isotypes, there have not been reported any lambda chain serological polymorphisms. [9]

All these before mentioned allotypes are expressed on constant regions of the immunoglobulin. Genes responsible for encoding structure of constant regions of heavy chains are closely linked and therefore inherited together as one haplotype with low number of crossovers. Although some crossovers did occur during human evolution resulting in the creation of current populations characteristic haplotypes and importance of allotype system in population studies. [10] , [11]

Implications for monoclonal antibody therapy

Antibody allotypes came back to spotlight due to development and use of therapies based on monoclonal antibodies. These recombinant human glycoproteins and proteins are now well established in clinical practise, but sometimes leads to adverse effects such as generation of antitherapeutic antibodies that negates therapy or even cause severe reactions to the therapy. This reaction may be attributed to differences between therapeutics itself or may arise between same therapeutics produced by different companies or even between different lots produced by the same company. To prevent production of such antitherapeutic antibodies, ideally, all clinical used proteins and glycoproteins should poses same allotype as natural patient’s product, this way the presence of ‘altered self‘ which poses a potential target for immune system, is limited. Whilst many parameters connected to developing and manufacturing process that might predispose monoclonal antibodies to cause immune response are well known and appropriate steps are taken to monitor and control these unwanted effects, complications linked with administration of monoclonal antibodies to genetically diverse human population are less well described. Humans exhibit abundance of genotypes and phenotypes, however all currently licensed IgG therapeutic immunoglobulins are developed as single allotypic/ polymorphic form. Patients that are homozygous for alternative phenotype are therefore at higher risk of developing potential immune response to the therapy. [4]

See also

Related Research Articles

Antibody Protein(s) forming a major part of an organisms immune system

An antibody (Ab), also known as an immunoglobulin (Ig), 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. Each tip of the "Y" of an antibody contains a paratope that is specific for one particular epitope 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.

Major histocompatibility complex Cell surface proteins, part of the acquired immune system

The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are called MHC molecules.

Immunoglobulin G (IgG) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG antibody has two paratopes.

Immunoglobulin D

Immunoglobulin D (IgD) is an antibody isotype that makes up about 1% of proteins in the plasma membranes of immature B-lymphocytes where it is usually co-expressed with another cell surface antibody called IgM. IgD is also produced in a secreted form that is found in very small amounts in blood serum, representing 0.25% of immunoglobulins in serum. The relative molecular mass and half-life of secreted IgD is 185 kDa and 2.8 days, respectively. Secreted IgD is produced as a monomeric antibody with two heavy chains of the delta (δ) class, and two Ig light chains.

Immunoglobulin M One of several isotypes of antibody

Immunoglobulin M (IgM) is one of several isotypes of antibody that are produced by vertebrates. IgM is the largest antibody, and it is the first antibody to appear in the response to initial exposure to an antigen. In humans and other mammals that have been studied, plasmablasts residing in the spleen are the main source for specific IgM production.

Immunoglobulin heavy chain Large polypeptide subunit of an antibody

The immunoglobulin heavy chain (IgH) is the large polypeptide subunit of an antibody (immunoglobulin). In human genome, the IgH gene loci are on chromosome 14.

Monoclonal antibody therapy Form of immunotherapy

Monoclonal antibody therapy is a form of immunotherapy that uses monoclonal antibodies (mAbs) to bind monospecifically to certain cells or proteins. The objective is that this treatment will stimulate the patient's immune system to attack those cells. Alternatively, in radioimmunotherapy a radioactive dose localizes a target cell line, delivering lethal chemical doses. Antibodies have been used to bind to molecules involved in T-cell regulation to remove inhibitory pathways that block T-cell responses. This is known as immune checkpoint therapy.

Fragment crystallizable region Tail region of an antibody

The fragment crystallizable region is the tail region of an antibody that interacts with cell surface receptors called Fc receptors and some proteins of the complement system. This property allows antibodies to activate the immune system. In IgG, IgA and IgD antibody isotypes, the Fc region is composed of two identical protein fragments, derived from the second and third constant domains of the antibody's two heavy chains; IgM and IgE Fc regions contain three heavy chain constant domains in each polypeptide chain. The Fc regions of IgGs bear a highly conserved N-glycosylation site. Glycosylation of the Fc fragment is essential for Fc receptor-mediated activity. The N-glycans attached to this site are predominantly core-fucosylated diantennary structures of the complex type. In addition, small amounts of these N-glycans also bear bisecting GlcNAc and α-2,6 linked sialic acid residues.

Immunoglobulin class switching Biological mechanism

Immunoglobulin class switching, also known as isotype switching, isotypic commutation or class-switch recombination (CSR), is a biological mechanism that changes a B cell's production of immunoglobulin from one type to another, such as from the isotype IgM to the isotype IgG. During this process, the constant-region portion of the antibody heavy chain is changed, but the variable region of the heavy chain stays the same. Since the variable region does not change, class switching does not affect antigen specificity. Instead, the antibody retains affinity for the same antigens, but can interact with different effector molecules.

Immunoglobulin light chain

The immunoglobulin light chain is the small polypeptide subunit of an antibody (immunoglobulin).

Isotype (immunology)

In immunology, antibodies are classified into several types called isotypes or classes. The variable (V) regions near the tip of the antibody can differ from molecule to molecule in countless ways, allowing it to specifically target an antigen . In contrast, the constant (C) regions only occur in a few variants, which define the antibody's class. Antibodies of different classes activate distinct effector mechanisms in response to an antigen . They appear at different stages of an immune response, differ in structural features, and in their location around the body.

KIR3DL1 Protein-coding gene in the species Homo sapiens

Killer cell immunoglobulin-like receptor 3DL1 is a protein that in humans is encoded by the KIR3DL1 gene.

IGHM Gene in the species Homo sapiens

Ig mu chain C region is a protein that in humans is encoded by the IGHM gene.

IGHG1

Ig gamma-1 chain C region is a protein that in humans is encoded by the IGHG1 gene.

LILRB4 Protein-coding gene in the species Homo sapiens

Leukocyte immunoglobulin-like receptor subfamily B member 4 is a protein that in humans is encoded by the LILRB4 gene.

Immunoglobulin heavy constant alpha 1 Gene in the species Homo sapiens

Immunoglobulin heavy constant alpha 1 is a immunoglobulin gene with symbol IGHA1. It encodes a constant (C) segment of Immunoglobulin A heavy chain. Immunoglobulin A is an antibody that plays a critical role in immune function in the mucous membranes. IgA shows the same typical structure of other antibody classes, with two heavy chains and two light chains, and four distinct domains: one variable region, and three variable regions. As a major class of immunoglobulin in body secretions, IgA plays a role in defending against infection, as well as preventing the access of foreign antigens to the immunologic system.

IGHG2 Gene in the species Homo sapiens

Ig gamma-2 chain C region is a protein that in humans is encoded by the IGHG2 gene.

FCGR2B

Fc fragment of IgG receptor IIb is a low affinity inhibitory receptor for the Fc region of immunoglobulin gamma (IgG). FCGR2B participates in the phagocytosis of immune complexes and in the regulation of antibody production by B lymphocytes.

Complement-dependent cytotoxicity (CDC) is an effector function of IgG and IgM antibodies. When they are bound to surface antigen on target cell, the classical complement pathway is triggered by bonding protein C1q to these antibodies, resulting in formation of a membrane attack complex (MAC) and target cell lysis.

The Vel blood group is a human blood group that has been implicated in hemolytic transfusion reactions. The blood group consists of a single antigen, the high-frequency Vel antigen, which is expressed on the surface of red blood cells. Individuals are typed as Vel-positive or Vel-negative depending on the presence of this antigen. The expression of the antigen in Vel-positive individuals is highly variable and can range from strong to weak. Individuals with the rare Vel-negative blood type develop anti-Vel antibodies when exposed to Vel-positive blood, which can cause transfusion reactions on subsequent exposures.

References

  1. ↑ "Pathology, Microbiology and Immunology". University of South Carolina School of Medicine. Retrieved 2020-09-06.
  2. ↑ Mage R, Lieberman R, Potter M, Terry WD (January 1973). "Immunoglobulin Allotypes". The Antigens. Academic Press. pp. 299–376. doi:10.1016/b978-0-12-635501-7.50010-1. ISBN   978-0-12-635501-7.
  3. ↑ de Lange GG (1989). "Polymorphisms of human immunoglobulins: Gm, Am, Em and Km allotypes". Experimental and Clinical Immunogenetics. 6 (1): 7–17. PMID   2698222.
  4. 1 2 3 Jefferis R, Lefranc MP (August 2009). "Human immunoglobulin allotypes: possible implications for immunogenicity". mAbs. 1 (4): 332–8. doi:10.4161/mabs.1.4.9122. PMC   2726606 . PMID   20073133.
  5. ↑ Fudenberg HH, Fudenberg BR (July 1964). "Antibody to Hereditary Human Gamma-Globulin (GM) Factor Resulting from Maternal-Fetal Incompatibility". Science. 145 (3628): 170–1. Bibcode:1964Sci...145..170F. doi:10.1126/science.145.3628.170. PMID   14171557. S2CID   42336232.
  6. ↑ Vidarsson G, Dekkers G, Rispens T (2014). "IgG subclasses and allotypes: from structure to effector functions". Frontiers in Immunology. 5: 520. doi: 10.3389/fimmu.2014.00520 . PMC   4202688 . PMID   25368619.
  7. ↑ International Union of Immunological Sciences (1974). "Recommendations for the Nomenclature of Human Immunoglobins". European Journal of Biochemistry. 45 (1): 5–6. doi: 10.1111/j.1432-1033.1974.tb03522.x .
  8. ↑ "Review of the Notation for the Allotypic and Related Markers of Human Immunoglobulins". International Journal of Immunogenetics. 3 (5): 357–362. 1976. doi:10.1111/j.1744-313X.1976.tb00595.x. S2CID   32562449.
  9. ↑ Ghanem N, Dariavach P, Bensmana M, Chibani J, Lefranc G, Lefranc MP (1988). "Polymorphism of immunoglobulin lambda constant region genes in populations from France, Lebanon and Tunisia". Experimental and Clinical Immunogenetics. 5 (4): 186–95. PMID   2908491.
  10. ↑ "IMGT Repertoire (IG and TR)". International ImMunoGeneTics Information System (IMGT). Retrieved 2020-09-06.
  11. ↑ Lefranc MP, Lefranc G (2012). "Human Gm, Km, and Am allotypes and their molecular characterization: a remarkable demonstration of polymorphism". Immunogenetics. Methods in Molecular Biology. Vol. 882. pp. 635–80. doi:10.1007/978-1-61779-842-9_34. ISBN   978-1-61779-841-2. PMID   22665258.


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