Page 100 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHAPtER 5 The Major Histocompatibility Complex 85

KEY CoNCEPtS an effective immune response to the particular pathogen.
Function of the Human Leukocyte Antigen Moreover, selection also operates on the pathogen, encouraging
peptide variation. Variation in peptides drawn from common
(HLA) Molecules pathogens and the introduction of novel pathogens with novel
• The HLA molecule is a receptor that binds a peptide. The peptide–HLA peptides result in pressure on the species to create variation in
complex is a ligand that binds to the clonotypic T-cell receptor (TCR). HLA molecules among individual members of that species. The
The trimolecular Peptide–HLA–TCR complex triggers the activation remarkably different frequency of the HLA alleles in different
and proliferation of the T cell in an adaptive immune response. ethnic subsets tells the history of the successful adaptation of
• HLA class I A, B, and C molecules are expressed on the surface our ancestors’ adaptive immune systems to a new environment
of virtually all nucleated cells. with different pathogens, as well as bottlenecks resulting from
• HLA class II DQ, DR, and DP molecules are constitutively expressed
on B cells, professional antigen-presenting cells (APCs), thymic migration and perhaps survival during periods of massive
epithelial cells, and activated T cells. epidemics.
• The immunological self is the set of self peptides and self HLA The evolutionary consequence of the diversification of genes
molecules that select the TCR repertoire in the thymus and that encoding HLA molecules is seen at two levels. The first is at the
constitute the T-cell recognition component of an individual’s adaptive level of the individual and is characterized by the presence of
immune system. different HLA class I and class II loci, each of which codes for
• Nonself peptide–HLA complexes are recognized by T cells during an one or two different peptide-presenting HLA molecules for each
adaptive immune response, and they become activated to either initiate
an immune response (CD4 helper T cells) or recognize a target (CD8 locus. The second is at the level of the population and is evidenced
cytotoxic T cells). by the development of a very large number of alleles at each
• Through thymic selection, the TCR can adapt to recognize a very large locus, with each allele coding for alternative polymorphic gene
variety of peptide–HLA structures. forms and thus for various peptide-presenting allotypes, each
• Because of the plasticity of this recognition, genes encoding the of which has the potential to bind a different set of peptides.
HLA molecules are free to evolve a large number of genes encoding Duplication of HLA genes involved in peptide presentation is a
duplicated or alternative peptide-presenting molecules with specificity
to bind different peptides. genetic strategy that increases the range of peptide-presenting
• The diversification of peptide-presenting structures fosters the structures available to the individual, thus enhancing the variety
development of different T-cell repertoires with completely different of presented peptides that can be recognized and bound. 8
recognition properties. This thwarts the possibility that a pathogen
will be able to evolve a way to bypass recognition.
KEY CoNCEPtS
The Biological Significance of Polymorphisms:
GENERATION AND SELECTION OF Why so Many?
POLYMORPHISMS: BIOLOGICAL CONSEQUENCES • Human leukocyte antigen (HLA) class I and class II genes are extremely
polymorphic.
The hallmark of the classic HLA molecules, both class I and • Each HLA allele encodes molecules with different peptide-binding
class II, is their extensive polymorphism. HLA polymorphism properties that influence the particular peptides recognized by the
observed in different human populations is far greater than any T cells.
other polymorphism observed in any other part of the human • The sequence of the HLA gene thereby determines the peptide
genome. This is a direct reflection of their role in the immune recognition features of the adaptive immune response.
response. Pathogens characterized by different proteins and • HLA allelic polymorphisms are maintained by frequency-dependent
peptides, either in different epidemics or endemic to regions, selection, where the fitness of an individual bearing a novel allele
account for much of the evolutionary drive responsible for the increases because it can respond more effectively to certain
pathogens.
large number of alternative gene forms and their regional diversity • The multiple loci and numerous alleles per locus serve both the fitness
across the human race. An individual with an adaptive immune of an individual and the survival of the species.
system based on HLA molecules that effectively bind peptides • The polymorphism of the HLA system reflects the environmental/
derived from common pathogens is much more likely to have pathogen challenges to which a particular population has been
an effective response against that common pathogen. This results exposed over evolutionary time.
in selection of individuals with a particular allele, encoded by
an HLA gene.
Genetic polymorphism implies that alleles of a gene are present HLAS IN INFECTIONS, TRANSPLANTATION,
at a frequency greater than expected from random mutation as AUTOIMMUNITY, AND CANCER
a result of selection for diversity. In the case of the HLA genes,
there is no preponderant wild-type allele, which would be an HLA in Infections
example of balancing selection. Instead, virtually all alleles qualify The first line of defense during infection by a pathogen is the
as genetically polymorphic. These reflect prior successful selection triggering of innate immunity (Chapter 3). The infectious agent
events. HLA polymorphisms provide a major evolutionary survival and the foreign peptides generated from that agent then initiate
benefit, since they equip the species with a large number of very an immune response involving immune cells and signals that
specific, but alternative, HLA molecules that differ in their binding subsequently induce adaptive immunity.
pockets, are most efficient in presenting different peptides, and During the course of an infection, specialized antigen-
selecting different T-cell repertoires. A polymorphism that offers presenting cells (APCs; DCs and macrophages) are activated to
survival advantage would eventually increase in frequency. This take up antigen. Increasing synthesis of class II coupled with
illustrates frequency-dependent selection, where the fitness of presentation of and pathogen’s peptides by class II to the immune
individuals bearing a particular allele increases, if they can manage system of the host drives CD4 T cells that recognize the HLA