The Evolution of Alloimmunity and the Genesis of Adaptive Immunity

Abstract

Infectious agents select for host immune responses that destroy infectious nonself yet maintain tolerance to self. Here we propose that retroviruses and other host-antigen associated pathogens (HAAPs) select for the genetic, biochemical, and cell biological properties of alloimmunity, also known as the histocompatibility or tissue rejection response. This hypothesis predicts the major observations regarding histocompatibility responses, including: (i) their existence in animals as diverse as sponges and humans; (ii) extreme polymorphism and balanced allele frequencies at histocompatibility loci, including the human MHC and blood group loci; (iii) the frequency dependent selection of histocompatibility alleles; (iv) the ancient age of many alloantigenic polymorphisms; (v) the high ratio of nonsynonymous mutations to synonymous mutations at histocompatibility loci; (vi) disassortative mating based on MHC alleles; (vii) the inability to explain the existence and continuing selection of histocompatibility alleles by other more conventional biochemical and genetic paradigms; and (viii) the susceptibility of HAAPs, particularly retroviruses such as HIV (human immunodeficiency virus), to histocompatibility reactions. In addition, the hypothesis that HAAPs select the forms and molecules of alloimmunity offers simple explanations for the evolution of histocompatibility systems over time, the initial selection of hypervariable immune mechanisms, and the genesis of adaptive immunity.

Deconvoluting Post-Transplant Immunity: Cell Subset-Specific Mapping Reveals Pathways for Activation and Expansion of Memory T, Monocytes and B Cells

“…The early inflammatory response is initiated by ischemia/reperfusion, activation of innate immunity and subsequent alloantigen-primed T cell recruitment, activation and proliferative expansion [1]–[5]. The early immune response creates a complex milieu that contributes significantly to the course of ensuing events and the ultimate outcome of the transplant including acute and chronic rejection [6]–[9].…”

The Vigor of Defense Against Non-Self: Potential Superiority of Allorestricted T Cells in Immunotherapy of Cancer?

“…In addition, infectious agents selected for host immune responses that destroy infectious non-self, yet maintain tolerance to self. Retroviruses and other pathogens may thus have simultaneously selected for alloimmunity (Gould et al, 2004), because polymorphism was primarily advantageous to the population and maybe secondary advantageous to the genetic integrity of the individual by providing allorecognition and allorejection.…”

The role of human leukocyte antigen class I polymorphism in HIV/AIDS

“…amino acid sequence with equivalent binding properties for these alleles) [34]. By the principle of frequency-dependent selection [35], infrequent supertype alleles might hypothetically be expected to generate the most favorable CTL responses. According to this hypothesis, a virus quasispecies would adapt better to the alleles whose binding properties it has encountered more commonly in a population.…”