Immunogenetics

Immunogenetics investigates how inherited genetic variation shapes the development, specificity and regulation of immune responses. Central to this field are the highly polymorphic human leucocyte antigen (HLA) genes, which encode major histocompatibility complex (MHC) proteins responsible for presenting pathogen- or self-derived peptides to T cells. Allelic diversity at HLA class I and class II loci underpins the breadth of antigen recognition and influences susceptibility to infection, autoimmunity, transplant compatibility and vaccine responsiveness. Beyond HLA, variation in immunoglobulin gene segments, cytokine and chemokine genes, complement components and pattern-recognition receptors all contribute to inter-individual differences in immune function. Somatic processes, such as V(D)J recombination, somatic hypermutation and class switch recombination, further diversify the antibody repertoire. Together, germline and somatic genetic mechanisms govern the balance between effective host defence and immunopathology, with practical applications in precision medicine, vaccine design, transplantation and disease risk stratification.

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Expansion of the minor histocompatibility antigen (MiHA) catalogue through in silico survey and immunopeptidomic analysis has identified over 150 HLA class I–restricted peptides differing between donor and recipient proteomes. Fourteen of these exhibit haematopoietic-restricted expression, informing strategies to harness selective graft-versus-leukaemia responses while reducing graft-versus-host disease.

Whole-genome sequencing and genome-wide association in neuromyelitis optica spectrum disorder (NMOSD) patients have defined two independent signals in the MHC region, one linked to structural variation in complement component 4 genes. Mendelian randomisation using systemic lupus erythematosus risk alleles has revealed shared genetic architecture with NMOSD, and admixture analyses in Mexican cohorts demonstrate that Native American ancestry contributes specific HLA-DRB1 and DQB1 susceptibility alleles.

Mechanistic studies of antibody diversification have uncovered a post-occupancy licensing step for activation-induced cytidine deaminase (AID). Mutation of a conserved AID arginine cluster abolishes association with transcription elongation factors without altering deaminase activity, uncoupling locus occupancy from productive mutagenesis during somatic hypermutation and class switch recombination. Additionally, the deubiquitinase Usp22 has been shown to facilitate γH2AX formation and classical non-homologous end joining, selectively affecting switching to particular immunoglobulin isotypes.

Immunogenetics publication trend

The graph below shows the total number of articles in immunogenetics across all publications each year (not limited to Nature Index journals).

Technical terms

HLA (Human Leucocyte Antigen): A set of highly polymorphic genes encoding MHC proteins that present peptide antigens to T cells.

Somatic Hypermutation (SHM): The introduction of point mutations into immunoglobulin variable regions in germinal centres to drive affinity maturation of antibodies.

Class Switch Recombination (CSR): The recombination process that replaces the immunoglobulin constant region gene, enabling a B cell to produce different antibody isotypes with unchanged specificity.

Minor Histocompatibility Antigen (MiHA): A peptide derived from polymorphic proteins that differ between transplant donor and recipient and can elicit T-cell responses.

Mendelian Randomisation: An analytical approach using genetic variants as instruments to infer causal relationships between risk factors and disease outcomes.

Non-homologous End Joining (NHEJ): A DNA repair pathway that ligates double-strand breaks without requiring extensive homology, critical for CSR and V(D)J recombination.

References

1. The Concept of Immunogenetics.
2. Systematic identification of minor histocompatibility antigens predicts outcomes of allogeneic hematopoietic cell transplantation. Nature Biotechnology (2024).
3. Multi-Level Analyses of Genome-Wide Association Study to Reveal Significant Risk Genes and Pathways in Neuromyelitis Optica Spectrum Disorder. Frontiers in Genetics (2021).
4. A whole-genome sequence study identifies genetic risk factors for neuromyelitis optica. Nature Communications (2018).
5. Native American ancestry significantly contributes to neuromyelitis optica susceptibility in the admixed Mexican population. Scientific Reports (2020).
6. A licensing step links AID to transcription elongation for mutagenesis in B cells. Nature Communications (2018).
7. The H2B deubiquitinase Usp22 promotes antibody class switch recombination by facilitating non-homologous end joining. Nature Communications (2018).