Chapter category: MHC
Mechanisms and Implications of Immunodominance
Minor Histocompatibility Antigens: From the Laboratory to the Clinic
Edited by: Derry C. RoopenianISBN: 1-57059-599-2
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Chapter authors:
Claude Perreault, Stéphane Pion and Denis C. Roy
Minor H antigens have two fundamental characteristics:
- they are MHC–associated self peptides derived from the partial proteolysis
of
endogenous proteins, and - they are polymorphic and immunogenic for T cells.1–7 Because of their polymorphism and immunogenicity, minor H antigens can trigger graft rejection or graft–versus–host disease (GVHD), and have therefore attracted considerable clinical interest.1,2,7,8
In order to assess the magnitude of the problem posed by minor H antigens in transplantation, the first questions that were addressed concerned the number of minor H loci and their level of polymorphism. As outlined in several chapters in this volume, minor H antigens generally originate from rare mutations affecting evolutionarily conserved protein sequences, and their polymorphism is low, most of them being encoded by biallelic loci.9–13
The question of the total number of minor H antigens is a complex issue and is still a matter of dispute. Theoretically, as a mutation in any gene could give rise to a new minor H antigen, the total number of minor H antigens harbored by an individual could be enormous.5 However, not every polymorphic sequence is expected to be immunogenic. In order to be immunogenic, polymorphic self–peptides must be adequately presented and recognized. This means that such a peptide must:
- be liberated from its precursor and not be destroyed,
- compete successfully with other peptides for binding to MHC molecules, and
- the resulting peptide/MHC complex must be recognized by a T–cell receptor (TCR).14–16
Furthermore, simultaneous presentation of both class I– and class II–associated epitopes on the same antigen presenting cell (APC) greatly influences the amplitude and consequences of T–cell activation.17,18 Estimates based on the frequency of minor H gene mutations and on the segregation of independent minor H genes in congenic mice suggest that two unrelated strains of mice, such as C57BL/6 and BALB.B, differ by at least 45 minor H loci, and that the total number of minor H genes could be in the range of 430–720.1,19 It was therefore a great surprise when CTL responses raised between different strains of mice were found to be targeted to an extremely limited number of minor H antigens, commonly 2 or 3.20–27 This phenomenon termed "immunodominance" signifies that some minor H antigens, said to be
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Claude Perreault, Stéphane Pion and Denis C. Roy
Minor H antigens have two fundamental characteristics:
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The mystery of the molecular nature of minor histocompatibility (H) antigens is solved: this volume, and the meeting that begot it, record both that fact and the uses to which this new know...
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Minor histocompatibility (H) antigens were first defined at the cellular level approxi-mately 50 years ago.1,2 Since then, over 50 distinct H loci have been identified b...
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My first research project in immunology was given to me in 1979 by Jan Klein at the Max Planck Institute for Biology in Tübingen. He explained to me what minor histo-compatibility (H) ant...
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Early studies in histocompatibility focused on the number of genes that evoke graft rejection. Initially, (H) genes were treated together as a set and the size of this set was the most importa...
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Histoincompatibility was first detected in mice at the beginning of the 20th century. The great majority of the loci responsible for this complex genetic trait are located on the autosomal chr...
