Immunoglobulin Allotypes

Antibody dependent cellular cytotoxicity (ADCC) is an Fc-dependent effector function of IgG important for anti-viral immunity and anti-tumor therapies. NK-cell mediated ADCC is mainly triggered by IgG-subclasses IgG1 and IgG3 through the IgG-Fc-receptor (FcγR) IIIa. Polymorphisms in the immunoglobulin gamma heavy chain gene likely form a layer of variation in the strength of the ADCC-response, but this has never been studied in detail. We produced all 27 known IgG allotypes and assessed FcγRIIIa binding and ADCC activity. While all IgG1, IgG2, and IgG4 allotypes behaved similarly within subclass, large allotype-specific variation was found for IgG3. ADCC capacity was affected by residues 291, 292, and 296 in the CH2 domain through altered affinity or avidity for FcγRIIIa. Furthermore, allotypic variation in hinge length affected ADCC, likely through altered proximity at the immunological synapse. Thus, these functional differences between IgG allotypes have important implications for therapeutic applications and susceptibility to infectious-, allo- or auto-immune diseases.

IntroductionThe human monoclonal antibody adalimumab is known to induce an anti-globulin response in some adalimumab-treated patients. Antibodies against adalimumab (AAA) are associated with non-response to treatment. Immunoglobulins, such as adalimumab, carry allotypes which represent slight differences in the amino acid sequences of the constant chains of an IgG molecule. Immunoglobulins with particular IgG (Gm) allotypes are racially distributed and could be immunogenic for individuals who do not express these allotypes. Therefore, we investigated whether a mismatch in IgG allotypes between adalimumab and IgG in adalimumab-treated patients is associated with the development of AAA.MethodsThis cohort study consisted of 250 adalimumab-treated rheumatoid arthritis (RA) patients. IgG allotypes were determined for adalimumab and for all patients. Anti-idiotype antibodies against adalimumab were measured with a regular radio immunoassay (RIA), and a newly developed bridging enzyme linked immunosorbent assay (ELISA) was used to measure anti-allotype antibodies against adalimumab. The association between AAA and the G1m3 and the G1m17 allotypes was determined. For differences between groups we used the independent or paired samples t-test, Mann-Whitney test or Chi square/Fisher's exact test as appropriate. To investigate the influence of confounders on the presence or absence of AAA a multiple logistic regression-analysis was used.ResultsAdalimumab carries the G1m17 allotype. No anti-allotype antibodies against adalimumab were detected. Thirty-nine out of 249 patients had anti-idiotype antibodies against adalimumab (16%). IgG allotypes of RA patients were associated with the frequency of AAA: patients homozygous for G1m17 had the highest frequency of AAA (41%), patients homozygous for G1m3 the lowest frequency (10%), and heterozygous patients' AAA frequency was 14% (P = 0.0001).ConclusionsAn allotype mismatch between adalimumab and IgG in adalimumab-treated patients did not lead to a higher frequency of AAA. On the contrary, patients who carried the same IgG allotype as present on the adalimumab IgG molecule, had the highest frequency of anti-adalimumab antibodies compared to patients whose IgG allotype differed from adalimumab. This suggests that the allotype of adalimumab may not be highly immunogenic. Furthermore, patients carrying the G1m17-allotype might be more prone to antibody responses.

BackgroundPlasmodium falciparum malaria is a complex disease in which genetic and environmental factors influence susceptibility. IgG isotypes are in part genetically controlled, and GM/KM allotypes are believed to be involved in this control.MethodsIn this study, 216 individuals from Daraweesh, an area of seasonal malaria transmission in Sudan, were followed for nine years for malaria infection. Total IgG and IgG isotypes against four malaria antigens, MSP2-3D7, MSP2-FC27, AMA1, and Pf332-C231 were measured in plasma obtained from the cohort at the end of the study, during the dry malaria-free period. The GM/KM allotypes of the donors were determined.ResultsThe GM 1,17 5,13,14,6 phenotype was associated with a higher incidence of malaria compared with the non-1,17 5,13,14,6 phenotypes (P = 0.037). Paradoxically, the carriers of the GM 1,17 5,13,14,6 phenotype had significantly higher baseline levels of total IgG and non-cytophilic IgG isotypes as compared to non-carriers. The KM allotypes influence on IgG isotypes level was limited. Finally, the differences in the baseline concentrations of total IgG and IgG isotypes between the different GK/KM phenotype carriers were antigen-dependent.DiscussionThe results show that GM but not KM allotypes appeared to influence host susceptibility to uncomplicated malaria as well as the antibody profile of the donors, and the carriers of the GM 1,17 5,13,14,6 phenotype were the most susceptibleConclusionsThe GM allotypes have significant influence on susceptibility to uncomplicated P. falciparum malaria and antigen-dependent influence on total IgG and IgG subclasses.

PURPOSE: IgG subclass genes from chromosome 14q32.3 are assessed serologically by GM allotypes, genetic markers of the Fc part of the immunoglobulin constant heavy G chains, (IGHG(Fcγ)(GM) genes. Alternative GM allotypes of IgG3, IgG1 and IgG2, respectively, define 6 unique, precise GM-specific IgG subclass genes, inherited the Mendelian way with allelic exclusion, and linkage disequilibrium of IgG3-IgG1. Increased number of homozygous GM-specific IgG subclass genotypes with total loss of alternative IgG subclass molecules, inborn errors of immunity (IEI), are found in severe immunological diseases. METHODS: A novel ELISA using GM-specific myeloma proteins and GM-specific monoclonals, identifies 6 alternative GM-specific IgG subclass genes and molecules IgG3*b & IgG3*g, IgG1*f & IgG1*a and IgG2*n & IgG2*-n, with different structures and functions. 4 different IgG3-IgG1-IgG2 haplotypes encode 10 individual IGHG diplotypes from 10 innate lymphoid combined B cells in 587 healthy. RESULTS: The alternative GM-specific IgG subclass genes have different structures and functions and respond differently in immunotherapy to antigen stimulation with virus, bacteria and allergens. In this report we focus on excluded GM-IgG subclass genes, inborn errors of immunity (IEI) dominating in severe immunological diseases, severe infections, primary immunodeficiencies (PIDs), JCA, asthma, diabetes type 1 and malignancy. By intravenous immunoglobulins (IVIG) the excluded IgG subclass molecules are supplied and may prevent primary virus attacks and exacerbations in autoimmune disorders. IgG subclass genes orchestrate additional immune factors of inflammation. CONCLUSION: Excluded GM-specific IgG subclass genes, IEI explore diagnosis, pathogenesis, prognosis and different phenotypes in immunological diseases, with IVIG as treatment.