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Immunoglobulins

Last modified August 23, 2017

Background

The existence of an agent in the blood that could neutralize diphteria toxin was reported as early as 1890. Over a century after this major discovery, much is known about immunoglobulins (IG) or antibodies. They are large heterodimeric proteins made up of 2 heavy (H) chains and 2 light (L) kappa or lambda chains, held together by disulfide bonds to form a ‘Y’ shaped molecule. Each chain comprises one variable (V) domain at the N-terminal end and one or several (for L and H, respectively) constant (C) domains. The antigen binding site is formed by the V domain of one H chain, together with that of its associated L chain. Thus, each immunoglobulin has 2 antigen binding sites with remarkable affinity for a particular antigen. Each variable domain is encoded by a variable (V) gene, a diversity (D) gene (only for H) and a joining (J) gene which are assembled by a process called V-(D)-J rearrangement and can then be subjected to somatic hypermutations which, after exposure to antigen and selection, allow affinity maturation for a particular antigen. The resulting rearranged V-(D)-J genes are further spliced to C genes. The C region determines the effector properties and the mechanism used to destroy the antigen, such as activation of complement or binding to Fc receptors.

An immunoglobulin is encoded by 7 genes (IGHV, IGHD, IGHJ, IGHC for the H chain and IGKV, IGKJ, IGKC for a kappa or IGLV, IGLJ or IGLC for a lambda L chain). The human genome contains 176 functional immunoglobulin genes clustered in 3 loci, IGH on chromosome 14 (50 V, 23 D, 6 J and 9 C), IGK on chromosome 2 (40 V, 5 J and 1 C) and IGL on chromosome 22 (32 V, 5 J and 5 C). During the development of B cells, the mechanisms of diversity involved in the immunoglobulin synthesis (combinatorial V-(D)-J diversity, junctional diversity and somatic hypermutations) lead to the huge potential antibody repertoire of each individual, estimated to comprise 1012 different immunoglobulins, the limiting factor being only the number of B cells that an organism is genetically programmed to produce.

Immunoglobulins in UniProtKB/Swiss-Prot

Work performed in collaboration with the IMGT team has included a thorough review and update of the immunoglobulin genes, for which UniProtKB/Swiss-Prot presents a representative set of full-length germline immunoglobulin protein sequences. 15 entries showing the sequence of all C regions and 122 representing all V regions are publicly available (release 2017_08). These entries can be retrieved with the keyword Immunoglobulin C region and Immunoglobulin V region, respectively. D and J gene products are extremely small, with an average of 5 amino acids for D genes and 15-30 for J. In other words, they are too short to be informative on their own. Therefore we have decided to curate a single peptide representative of D gene products and 3 of J gene products, one for H chains and 2 for L chains kappa and lambda. As for other human proteins, the sequences shown match the translation of the reference genome (Genome Reference Consortium GRCh38/hg38). The nomenclature used is the official one from IMGT/GENE-DB proposed by IMGT, approved by HGNC and endorsed by NCBI Gene and the IUIS-Nomenclature SubCommittee.

Cross-references to IMGT/Gene-DB

Cross-references to IMGT/Gene-DB in UniProtKB/Swiss-Prot immunoglobulin entries, provide direct access to the dedicated IMGT® resource and its comprehensive sequence repertoire, which describes almost 100 alleles from 462 functional and non-functional genes together with a wealth of additional information concerning immunoglobulins (Aug 2017). Reciprocal links to UniProtKB from IMGT ensure easy navigation between both resources.

Non-germline immunoglobulins

We also provide several examples of full-length non-germline immunoglobulins. Among the 1012 predicted sequences, we have selected some of those that have been entirely sequenced at the amino acid level. However, their representation is beyond the scope of our knowledgebase and UniProtKB users interested in these complex molecules are advised to visit IMGT.