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peptides to CD8+ T-cells

peptides to CD4+ cells

the context of class I, whereas helper/inducer cells (CD4+) usually recognize antigen in the context of the class II molecules.

Many immunologically mediated diseases, including certain endocrine syndromes, are genetically associated with specific HLA molecules and several hypotheses have been suggested to explain HLA-disease associations (59,60). Four of these general hypotheses apply to diseases associated with both class I and class II molecules. First, the antigen-binding cleft of a specific HLA molecule can accept antigenic peptides that other molecules cannot accept. These peptides can be either exogenous (e.g., a viral particle) or endogenous (e.g., an autoantigen). Those peptides that can be processed by the antigen-presenting cell (APC) are ultimately responsible for the generation of an immune response directed against the antigenic peptide. If this is a self peptide, an antiself (e.g., autoimmune) reaction will be activated. The second hypothesis suggests that a- and P-chains of the T-cell receptor (TCR) are the target of foreign molecules capable of potently stimulating T-cells by binding the TCR outside the HLA-peptide-TCR complex. Because the TCR carrying a certain P-chain is recognized by specific proteins

Fig. 2. Secondary structure of HLA class I and class II molecules in comparison. As is the case for immunoglobulins, peptidic sequences that show similarities and are present more than once in the same polypeptidic chain are called "domains." aj, a2, and a3 constitute the domains of the class I a-chain, whereas Pi and p2 are the domains of the class II P-chain as ai and a2 are the domains characteristic of the class II a-chain. Both class I and class II molecules are composed of noncovalently bound and somewhat different a- and P-chains. These heterodimers form, at their most external end, a peptide-combining site composed of the a1 and a2 domains for class I and a1 and p1 domains for class II molecules. The nonpolymorphic P2-microglobulin completes the structure of class I molecules. (Modified from ref. 193.)

Fig. 2. Secondary structure of HLA class I and class II molecules in comparison. As is the case for immunoglobulins, peptidic sequences that show similarities and are present more than once in the same polypeptidic chain are called "domains." aj, a2, and a3 constitute the domains of the class I a-chain, whereas Pi and p2 are the domains of the class II P-chain as ai and a2 are the domains characteristic of the class II a-chain. Both class I and class II molecules are composed of noncovalently bound and somewhat different a- and P-chains. These heterodimers form, at their most external end, a peptide-combining site composed of the a1 and a2 domains for class I and a1 and p1 domains for class II molecules. The nonpolymorphic P2-microglobulin completes the structure of class I molecules. (Modified from ref. 193.)

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Residue 52 of the a chain

Residue 57 of the (3 chain

Fig. 3. The two outermost domains of HLA class I and class II molecules fold together to form their antigen-combining sites in which the processed antigenic peptide can find appropriate lodging. The polymorphic regions of the HLA molecule seen from the top, present on the floor, and on the a-helices of its groove, are indicated in different nuances of color from gray to black. The antigenic peptides found in HLA class I molecule grooves are normally nine amino acids long, whereas the antigenic peptides most frequently found associated with HLA class II molecules are longer than nine amino acids and can vary considerably in size. The position of the amino acid 52 of the a-chain and that of the P-chain in position 57 are indicated. (Modified from ref. 22.)

that are products of bacterial or viral invaders (e.g., superantigens) in the context of a particular HLA molecule, these superantigens may trigger the generation of an immune response directed against self antigens, by nonspecifically activating autoreactive T-cell clones. The third hypothesis postulates that a TAP gene product, which normally transports antigenic peptides from the cytoplasm to the endoplasmic reticulum, is defective and, therefore, this predisposes to disease susceptibility. As a result of a defective TAP gene product, few peptides become available for binding to class I molecules, leading to a low surface density of class I-peptide complexes and to a high surface density of empty class I molecules. A high density of empty surface class I molecules may bind peptides to which they would otherwise not be exposed intracellularly—for instance, viral or bacterial peptides. These newly formed class I-exogenous peptide complexes may account for an induction of an immune response that can be responsible for disease. The fourth hypothesis, termed "molecular mimicry," implies that a foreign antigen such as a viral or bacterial antigen shares similarities with a self molecule, and because of this similarity, the immune response is turned against self target tissues, causing an autoimmune response.

Alleles at multiple loci on a single chromosome are usually inherited in combination as a unit. This combination of multiple genes inherited together is termed "haplotype." Because each individual inherits one set of chromosomes from each parent, each individual has two haplotypes for a given physical genetic interval. HLA genes are codom-inant and follow a simple Mendelian form of transmission in families (see Fig. 4). Therefore, as a consequence of HLA codominance, both alleles (one on each chromosome) are expressed from a given HLA locus. There is a 25% chance that two siblings share both haplotypes and are immunologically compatible, a 50% chance that they will share only one haplotype, and a 25% chance that they share no haplotype and, thus, are HLA different.

Certain combinations of HLA alleles are found with a frequency greater than expected and, consequently, they are not randomly distributed within the general population. This phenomenon is known as linkage disequilibrium and it is quantified by the difference (A) between the observed and the expected frequencies of a certain allele. One example is given by the HLA-A*0101 and the HLA-B*0801 alleles, which are found in Caucasian populations with frequencies of 0.161 and 0.104, respectively. Thus, the expected frequency of the HLA-A*0101, HLA-B*0801 haplotype should be 0.161 x 0.104 = 0.0167, but the frequency of this haplotype is instead 0.0592, which is almost four times the expected frequency (A = 0.0592 - 0.0167 = 0.0425).

The observation of linkage disequilibrium and extended haplotype inheritance is still a subject of discussion regarding the reason for its existence. One hypothesis that could explain linkage disequilibrium is that some haplotypes are preferentially protected from genetic recombination and, therefore, are preserved (ancestral haplotypes) (61,62). The mechanism underlying preservation of HLA haplotypes is not clear, but inhibition of crossing over during gametic meiosis may, in part, explain the cause of gene haplotype associations. Another hypothesis to explain the phenomenon of linkage disequilibrium is that certain haplotypes are preferentially reconstituted by recombination, even though this hypothesis may not completely explain the phenomenon (63). A third, evolution-based "Darwinian" hypothesis holds that certain HLA haplotypes confer a certain advantage and are favored by natural selection (64).

Fig. 4. The study of the segregation of HLA alleles through a family is based on the determination of the HLA phenotypes on at least the two parents and a child or on three HLA-different members of the same family. Segregation analysis allows the definition of the four haplotypes (normally called a, b, c, and d) present in the family and, consequently, the definition of individuals heterozygous or homozygous at certain loci (e.g., sibling 1 is homozygous at C, DR, and DP loci, both alleles are white; but heterozygous at A, B, and DQ loci, 1 white and 1 black allele), together with the recognition of individuals who share one haplotype only (e.g., siblings 1 and 2 are haploidentical because they share the "a" haplotype), or two haplotypes (e.g., siblings 2 and 6 are HLA identical because they share the "a" and the "d" haplotypes), or none (e.g., siblings 2 and 3, or 1 and 4 are HLA different). Although it is considered a very rare event, it is possible to find individuals, represented here by sibling 5, in which a crossing over between class I and class II gene regions, involving the paternal and maternal haplotypes of the father of this family, cause the "a-b" recombination flagged here with an asterisk (b*). (Modified from ref. 193.)

Fig. 4. The study of the segregation of HLA alleles through a family is based on the determination of the HLA phenotypes on at least the two parents and a child or on three HLA-different members of the same family. Segregation analysis allows the definition of the four haplotypes (normally called a, b, c, and d) present in the family and, consequently, the definition of individuals heterozygous or homozygous at certain loci (e.g., sibling 1 is homozygous at C, DR, and DP loci, both alleles are white; but heterozygous at A, B, and DQ loci, 1 white and 1 black allele), together with the recognition of individuals who share one haplotype only (e.g., siblings 1 and 2 are haploidentical because they share the "a" haplotype), or two haplotypes (e.g., siblings 2 and 6 are HLA identical because they share the "a" and the "d" haplotypes), or none (e.g., siblings 2 and 3, or 1 and 4 are HLA different). Although it is considered a very rare event, it is possible to find individuals, represented here by sibling 5, in which a crossing over between class I and class II gene regions, involving the paternal and maternal haplotypes of the father of this family, cause the "a-b" recombination flagged here with an asterisk (b*). (Modified from ref. 193.)

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