Genetic Control Of Immune Response Research Articles

HLA II genes distribution in Epstein–Barr virus-associated nasopharyngeal carcinoma and other tumors of the oral cavity patients in Russia

Background. It has been proved that for the nasopharyngeal carcinoma (NPC) the etiological agent is the Epstein–Barr virus (EBV). Being an ubiquitous infection, EBV, under certain conditions, is able to display its oncogenic potential. Among a wide range of tumors associated with EBV, the NPC occupies a special place because it is characterized by a geographically and ethnically heterogeneous distribution, suggesting that in the pathogenesis of NPC, in addition to EBV, an important role is played by other factors, such as genetic predisposition to this neoplasm. Among known genetic factors influencing the frequency of NPC development, the human leukocyte antigen (HLA) complex occupies an important place, as it plays a central role in the presentation of viral antigens to the immune system. In Russia, the association of HLA alleles with the risk of EBV associated forms of NPC development and with development of other oral cavity tumors (OOCT), not associated with the virus, has not been studied. In the literature there are contradictory information about HLA genes, which determine the predisposition to the emergence of these tumors, and their role in the initiation and formation an immune response to EBV proteins. Objective: to study the distribution of the of DQA1-, DQB1-, DRB1-HLA class II gene variants associated with respectively the risk or resistance to the development of NPC and OOCT and with a high and low level of antibody response to EBV main proteins. A group of healthy persons served as a control. Materials and methods. Blood samples from 62 patients with NPC, 44 patients with OOCT, and as control, 300 healthy individuals, were used in the study. The blood serum samples of NPC and OOCT patients were tested for the presence of immunoglobulin classes G and A antibodies to capsid and early EBV antigens by indirect immunofluorescence. All serum samples of patients and healthy individuals were genotyped on HLA-DQA1, -DQB1 and -DRB1 by the method of multi-primer amplification by sequence-specific primers by real-time polymerase chain reaction. Results. In NPC patients, an increase in the frequency of HLA-DRB1*08 was found when compared with the frequency of a similar allele in healthy individuals (5.6 % vs 1.8 %; odds ratio (OR) 3.2; 95 % confidence interval (CI) 1.1–9.1; p = 0.02), and, on the contrary, a lower HLA-DQB1*0301 frequency was detected (16.1 % vs 25.3 %; p <0.05) than in healthy individuals. The data obtained suggest that the HLA-DRB1*08 gene is associated with an increased sensitivity to NPC. In OOCT patients, HLA-DQB1*0502–4 and HLA-DRB1*16 variants were less common than in healthy individuals (1.1 % vs 6.8 %; p <0.05 and 1.1 % vs 6.7 %; OR 0.16; 95 % CI 0.01–1.08; p <0.05, respectively), suggesting that the HLA-DQB1*0301 gene is associated with resistance to NPC, and HLA-DQB1*0502–4 and HLA-DRB1*16 variants – with resistance to OOCT. It is interesting to note the difference in the frequency of HLA-DRB1*13 between NPC and OOCT patients (17.7 % vs 6.8 %; OR 2.9; 95 % CI 1.1–8.6; p <0.05). One can suggest that this difference is related to the proven involvement of EBV in the NPC development. There were no other differences in the frequencies of class II HLA genes between the groups of NPC and OOCT patients. For the first time in Russia the importance of alleles DQA1, DQB1 and DRB1 of the HLA gene for the NPC and OOCT development, malignant tumors, respectively associated and non-associated with EBV, was studied. The results of the investigation completed together with known literature data allow us to conclude that the above alleles of the HLA class II gene can serve as a factor predisposing to the development of NPC in Russia. Conclusion. However, in order to establish a strict association between a specific HLA haplotype and the NPC and OOCT incidence, the information obtained is insufficient due to the complexity and variability of the genetic control of immune responses controlling the tumor process. A comprehensive study of this issue using different immune response genes and populations of different ethnic origins will probably help to elucidate the effect of genetic polymorphism on the risk of NPC and OOCT development in Russia.

Genetic Control of Immune Response and Susceptibility to Infectious Diseases

1 Department of Biotechnology, Center for Biosciences and Biotechnology, State University of Norte Fluminense Darcy Ribeiro, 28013-602 Campos dos Goytacazes, RJ, Brazil 2 Emory Vaccine Center, Yerkes National, Primate Research Center, Emory University, Atlanta, GA 30329, USA 3 Laboratory of Immunogenetics, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, 05508-900 Sao Paulo, SP, Brazil 4Department of Pediatrics, School of Medicine of Campos, Alvaro Alvim School Hospital, 28035-211 Campos dos Goytacazes, RJ, Brazil

Genetic control of immune responses to influenza A matrix 2 protein (M2)

Vaccines should protect genetically diverse populations. Therefore we tested the candidate “universal” influenza A matrix protein 2 (M2) vaccine in multiple mouse strains. Mice were primed with M2 DNA and boosted with M2 recombinant adenovirus (rAd). C57BL/6 (B6) mice developed no antibody or T-cell response to M2, while BALB/c responded strongly. CBA responses were intermediate. Both MHC and background genes influenced responsiveness. To improve low responses we immunized with adjuvanted peptide-carrier conjugates, or co-immunized with nucleoprotein (NP), which can augment T-cell help. The conjugate vaccine enhanced some outcomes but not others. Co-immunizing with NP improved outcomes over either NP or M2 immunizations alone. These results have implications for vaccination of genetically diverse populations.

HLA class I alleles tag HLA-DRB1 * 1501 haplotypes for differential risk in multiple sclerosis susceptibility

The major locus for multiple sclerosis (MS) susceptibility is located within the class II region of the Major Histocompatibility Complex (MHC). HLA-DRB1 alleles, constituting the strongest MS susceptibility factors, have been widely exploited in research including construction of transgenic animal models of MS. Many studies have concluded that HLA-DRB1*15 allele itself determines MS-associated susceptibility. If this were true, haplotypes bearing this allele would confer equal risk. If HLA-DRB1*15 bearing haplotypes differed for risk, roles for other loci in this region would be implied and further study of the fine structure of this locus would be compelling. We have tested the hypothesis comparing haplotypes stratified by HLA class I tagging. We show here that HLA-DRB1*15-bearing-haplotypes in 1970 individuals from 494 MS families are indeed heterogeneous. Some HLA-DRB1*15 haplotypes determine susceptibility while others do not. Three groups of class I tagged HLA-DRB1*15 haplotypes were not over-transmitted: (i) HLA-DRB1*15-HLA-B*08 (TR = 25, NT = 23, Odds Ratio = 1.09), (ii) -HLA-B*27 (TR = 18, NT = 17, Odds Ratio = 1.06), and (iii) rare HLA-DRB1*15 haplotypes (frequency <0.02). Rare haplotypes were significantly different from common haplotypes, and transmissions were remarkably similar to those for class-I-matched non-HLA-DRB1*15 haplotypes. These results unambiguously indicate that HLA-DRB1*15 is part of a susceptibility haplotype but cannot be the susceptibility allele itself, requiring either epistatic interactions, epigenetic modifications on some haplotypes, or nearby structural variation. These findings strongly imply that differences among HLA-DRB1*15 haplotypes will furnish the basis for MHC-associated susceptibility in MS and raise the possibility that the MHC haplotype is the fundamental unit of genetic control of immune response.

Molecular recognition of botulinum neurotoxin B heavy chain by human antibodies from cervical dystonia patients that develop immunoresistance to toxin treatment

We determined the entire profile of the continuous antigenic regions recognized by blocking antibodies (Abs) in sera from 30BoNT/B-treated cervical dystonia (CD) patients who developed unresponsiveness to treatment. The sera protected mice against a lethal dose of BoNT/B. We analyzed Ab binding to a panel of 60 synthetic 19-residue peptides (peptide C31 was 24 residues) that overlapped consecutively by 5 residues and encompassed the entire BoNT/B heavy (H) chain (residues 442-1291). Most Abs recognized a limited set of peptides but the pattern and Ab levels bound varied with the patient, consistent with genetic control of immune responses and with responses to each epitope being separately controlled. Abs were bound by peptides (in decreasing order): C1 (residues 848-866), C10 (974-992), C16 (1058-1076), C14 (1030-1048), N15 (638-656), N21/N22 (722-740/736-754), N24/N25 (764-782/778-796) and N29 (834-852). Peptides N3/N4 (470-488/484-502), N27 (806-824), C2 (862-880), C4 (890-908), C6/C7 (918-936/932-950), C17 (1072-1090), C24 (1170-1188), C29 (1240-1258) and C31 (1268-1291) exhibited low Ab binding. The remaining peptides bound little or no Abs. Of the 30 antisera, 28 (93.3%) had Abs that bound to peptides C1, C10, C14 or C16, and 27 (90.0%) bound to peptide N22. No peptide was recognized by all the antisera, but peptide combinations N24+C1, N22+N24+C1, N24+C1+C10, C10+C14+C16, N22+N24+C1+C10, C1+C10+C14+C16 or N22+N24+C1+C10+C14 bound blocking Abs in 30 (100%) antisera. BoNT/B-treated CD patients had higher Ab levels and bound to more epitopes (at least 11) than did BoNT/A-treated patients (5 regions). The regions recognized by anti-BoNT/B Abs occupied surface areas that displayed no correlation to surface electrostatic potential, hydrophilicity, hydrophobicity, or temperature factor. These regions afford candidates for epitope-specific manipulation of anti-toxin immune responses.

Latitudinal variation of immune defense and sickness behavior in the white-crowned sparrow (Zonotrichia leucophrys)

There is a general trend that parasitism risk declines as latitude increases. Host populations breeding at high latitudes should therefore invest less in costly immune defenses than populations breeding in temperate or tropical zones, although it is unknown if such an effect is mediated by environmental (photoperiodic) or genetic factors or both. Acquired immune function (humoral, cell-mediated) and behavioral sickness responses to lipopolysaccharide (LPS; mimics bacterial infection) were assessed in two subspecies of white-crowned sparrow (Zonotrichia leucophrys) that breed at different latitudes in western North America. Zonotrichia l. gambelii (GWCS) is a high-latitude breeder (47–68°N) while Z. l. pugetensis (PWCS) breeds at temperate latitudes (40–49°N). Captive males of each subspecies were acclimated to (1) a short day (non-breeding) photoperiod (8L:16D), (2) the breeding photoperiod of PWCS (16L:8D), or (3) the breeding photoperiod of GWCS (20L:4D). Photoperiod was manipulated because shorter day lengths may enhance immune function. In support of a genetic effect, humoral responses to diphtheria–tetanus vaccination were significantly higher in PWCS compared to GWCS, regardless of photoperiod. There were no differences in cell-mediated responses to phytohemagglutinin (PHA) between subspecies or among photoperiods. For sickness responses to LPS, a significant interaction between photoperiod and subspecies was found, with long day GWCS producing stronger sickness responses (losing more weight, eating less) than short day GWCS and PWCS on all day lengths. However, these effects were influenced by photoperiodic changes in body condition. In conclusion, we find evidence for genetic control of immune responses across latitude, but no support for environmental (photoperiodic) regulation.

Genetic Control of Immune Response in Carriers of the 8.1 Ancestral Haplotype

Ancestral haplotype (AH) 8.1(HLA-A1, Cw7, B8, TNFAB*a2b3, TNFN*S, C2*C, Bf*s, C4A*Q0, C4B*1, DRB1*0301, DRB3*0101, DQA1*0501, DQB1*0201) seems to be associated with susceptibility to autoimmune diseases. Different mechanisms are probably involved in increasing autoimmunity, such as unbalanced cytokine production and the lack of C4A protein. So AH 8.1 modifies immune response in many ways. In this study we demonstrate that IgG2 serum levels were significantly lower in 8.1 AH carriers than in 8.1 AH non-carriers. On the contrary, as regards IgG1, IgG3, IgG4 serum levels, no significant differences were observed between the two groups. In AH 8.1 carriers low IgG2 levels might take to slower clearance of the infectious agent and hence to a lasting presence of it. The persistence of infectious antigens could determine an increased production of autoantibodies with a higher risk of cross-reactions.

Genetic Control of Immune Response in Carriers of Ancestral Haplotype 8.1

In all caucasian populations the association of an impressive number of autoimmune diseases with genes from the HLA-B8, DR3 haplotype that is part of the ancestral haplotype (AH) 8.1 HLA-A1, Cw7, B8, TNFAB*a2b3, TNFN*S, C2*C, Bf*s, C4A*Q0, C4B*1, DRB1*0301, DRB3*0101, DQA1*0501, DQB1*0201 has been reported by different research groups. This haplotype, which is more common in northern Europe, is also associated with a number of immune system dysfunctions in healthy subjects. Analyzing the data according to gender, some dysfunctions are observed in women but not in men, in agreement with the role of X-linked genes and/or estrogens in the development and progression of autoimmune diseases. It has been proposed that a small number of genes within the 8.1 AH modify immune responsiveness and hence affect multiple immunopathological diseases. In this article, we demonstrate that neutrophil chemotaxis is significantly decreased in carriers of this AH, suggesting that this impairment may also be related to the increased occurrence of autoimmune diseases in these individuals.

Genetic regulation of host responses to Group A Streptococcus in mice

The group A streptococci (GAS, Streptococcus pyogenes) are important human pathogens which can cause a variety of diseases, ranging from mild infections to very severe invasive diseases. In recent years, evidence has been accumulated that host genetic factors have a major influence on the outcome of streptococcal infections. Variability in the degree of susceptibility of different inbred mouse strains to infection with GAS has demonstrated that the host genetic background largely determines the susceptibility of mice to this pathogen. This information is particularly useful for studying the immune mechanisms underlying disease susceptibility in mice, and provides an entry point for the identification of host defence loci. This paper reviews the recent advances in the characterisation of pathogenic mechanisms associated with the development of GAS-induced septic shock in the mouse model and outlines the current knowledge regarding the genetic control of immune responses to Group A streptococcus in mice.

From Proteins and Protein Models to Their Use in Immunology and Immunotherapy

The two leitmotifs of my scientific research were synthetic polymeric models of proteins and the structure of proteins as reflected by the three-dimensional conformation controlled by their amino acid sequence. This in turn led me to synthetic polypeptide antigens and to investigation of antibodies, ultimately resulting in the discovery of the determinant-specific genetic control of immune response and to the development of a therapeutic vaccine against the exacerbating-remitting form of multiple sclerosis. In protein chemistry I had two great teachers who became very close friends, Ephraim Katchalski-Katzir and Christian B. Anfinsen (Fig. 1), but in immunology I lacked the benefit of a great mentor, and so to some extent I was self-taught. Thus, I had to “figure out” many things myself.

Drosophila immunity: genes on the third chromosome required for the response to bacterial infection.

We have screened the third chromosome of Drosophila melanogaster for mutations that prevent the normal immune response. We identified mutant lines on the basis of their failure to induce transcription of an antibacterial peptide gene in response to infection or their failure to form melanized clots at the site of wounding. These mutations define 14 genes [immune response deficient (ird) genes] that have distinct roles in the immune response. We have identified the molecular basis of several ird phenotypes. Two genes, scribble and kurtz/modulo, affect the cellular organization of the fat body, the tissue responsible for antimicrobial peptide production. Two ird genes encode components of the signaling pathways that mediate responses to bacterial infection, a Drosophila gene encoding a homolog of I kappa B kinase (DmIkk beta) and Relish, a Rel-family transcription factor. These genetic studies should provide a basis for a comprehensive understanding of the genetic control of immune responses in Drosophila.

Genetic control of immune response to recombinant antigens carried by an attenuated Salmonella typhimurium vaccine strain: Nramp1 influences T-helper subset responses and protection against leishmanial challenge.

Attenuated strains of Salmonella typhimurium have been widely used as vehicles for delivery and expression of vaccine antigens in murine models of infectious disease. In mice, early bacterial replication following infection with S. typhimurium is controlled by the gene (Nramp1, formerly Ity/Lsh/Bcg) encoding the natural-resistance-associated macrophage protein (Nramp1). Nramp1 regulates macrophage activation and has multiple pleiotropic effects, including regulation of tumor necrosis factor alpha, interleukin 1beta (IL-1beta), and major histocompatibility complex class II molecules, all of which influence antigen processing and presentation. Nramp1 also has a direct effect on antigen processing, possibly by regulating the activity of proteases in the late endosomal compartment. Hence, there are multiple ways (regulation of bacterial load or recombinant antigen dose, class II molecule expression, costimulatory or adjuvant activity, and antigen processing) that Nramp1 might influence responses to recombinant salmonella vaccines. To test the hypothesis that Nramp1 influences responses to vaccination, congenic mouse strains have been used to analyze immune responses to recombinant antigens (tetanus toxoid antigen and leishmanial gp63) carried by live attenuated S. typhimurium aroA aroD mutants. Results show that congenic mice carrying the wild-type (S. typhimurium resistance) Nramp1 allele mount a predominantly T-helper-1 (IL-2 and gamma interferon) response to vaccination and show enhanced resolution of lesions following challenge infection with Leishmania major. In contrast, mice carrying mutant (S. typhimurium susceptibility) Nramp1 mount a T-helper-2 (immunoglobulin E and IL-4) response and show exacerbated lesion growth upon challenge.

Genetic control of immune responsiveness, aging and tumor incidence

Age-related alterations of the immune system affect both antibody and cell-mediated immune responses, T-cell responses being more severely affected than B-cell responses. Within the T-cell population, aging leads to replacement of virgin by memory cells and to accumulation of cells with signal transduction defects. Changes in T-cell subsets and in cytokine production profiles may produce suitable conditions for T-cell-mediated disregulation of antibody responses characterized by the production of low affinity and self-reactive antibodies. Also B-cells exhibit intrinsic defects and natural killer (NK) cell activity a profound loss in old mice. Whether age-related immune disfunctions influence life span and tumor incidence has been examined in mice genetically selected for high or low antibody responsiveness. It has been found that genetic selection of vigorous antibody responses in most cases produces mice with longer life span and lower lymphoma incidence. Moreover, the results of genetic segregation experiments indicate that antibody responsiveness and life span are polygenic traits regulated by a small number of the same or closely linked loci. Mice genetically selected for high or low mitotic responsiveness to PHA exhibit low or high tumor incidence, respectively, but no difference in life span, suggesting that T-cell activity is restricted to immune surveillance of neoplastic transformation. Studies on mice genetically selected for resistance or sensitivity to chemical carcinogenesis have uncovered loci that control both resistance to tumor induction and longevity while have no effects on immunity and disease incidence. Thus, the relative role of the immune system in conditioning the duration and the biological quality of life remains to be determined.

Evidence for genetic control of vaccine-induced antibody responses in cattle

The purpose of our study was to identify evidence for genetic control of immune responses in cattle. To address this question, we evaluated the variation of antibody responses induced by vaccination with Brucella abortus Strain 19, a live attenuated bacterial vaccine, in large half-sibling families. The data were analyzed using a parametric statistical model that incorporated the effects of sire, bovine major histocompatibility complex (BoLA) types and parameters related to the experimental design. The BoLA types represented a readily identifiable marker, analogous to those known to be associated with genetic control of immune responses in other mammals. Variation between individual animals within our test population was significant but we were able to identify both individual animals and families with high or low antibody production phenotypes. In several cases, these traits were significantly correlated with individual bulls, suggesting the existence of sire effects, or with individual BoLA types. These findings are consistent with the theory that at least two separate genes or genetic systems contribute to the control of bovine antibody responses to B. abortus vaccination. These genetic effects are likely to be analogous to those identified in several species of laboratory rodents and humans.

Ageing and genetic control of immune responsiveness

Ageing is associated with a progressive decline of immune responsiveness to exogenous antigens and increasing incidence of autoimmune phenomena [1,2]. Many studies have been focussed on the mechanisms of the immunologic features of ageing. Alterations in cellular components of the immune system rather than in the extracellular milieu seem to account for most of the variations of immune competence in ageing [3].

Genetic control of immune responses to the 18-kDa protein of Mycobacterium leprae: Different T H1 subsets may be involved in proliferative and delayed-type hypersensitivity responses

In vitro and in vivo responses to the 18-kDa protein of Mycobacterium leprae have been analysed in different strains of mice. Lymphocytes from BALB/cJ (H-2 d), BALB.B (H-2 b), B10.BR (H-2 k), and B10.M (H-2 f) mice primed with 18-kDa protein yielded high T cell proliferative responses, while those from C57BL/10J (H-2 b) mice yielded lower responses. Both H-2 and non-H-2 genes contributed to the magnitude of responsiveness. F 1 mice from high and low responder strains showed high responsiveness to the 18-kDa protein. Supernatants from lymph node cell cultures prepared from 18-kDa protein-immunised BALB/cJ, B10.BR, and C57BL/10J mice contained IL-2 but no IL-4, indicating that activated T cells from both high and low responder mice were of a T H1 phenotype. Cell cultures from low responder C57BL/10J mice produced less IL-2 than those from high responders. The low responsiveness to the 18-kDa protein in proliferative assays might be due to a low frequency of antigen-specific T cells in the C57BL/10J mouse strain. BALB/cJ, C57BL/10J, and F 1 (BALB/cJ X B10.BR) mouse strains were tested for in vivo DTH reactions to the 18-kDa protein. All strains, including C57BL/10J, were high DTH responders. Although DTH effector cells and 18-kDa protein-specific proliferative T cells belong to the T H1 subset, our data comparing high and low responder status indicate that distinct T H1 subpopulations are stimulated in response to the 18-kDa protein of M. leprae.

Genetic control of immune responses in mice to synthetic peptides of a Streptococcus mutans surface protein antigen.

The immune responses to a cell surface protein antigen (PAc) of Streptococcus mutans and a peptide corresponding to residues 301 to 319 of the protein antigen [PAc(301-319)] in various strains of mice were studied, with attention being given to the haplotype of major histocompatibility complex (MHC) class II genes. Subcutaneous immunization of mice carrying the MHC class II I-Ad gene [BALB/c, B10.D2, B10.GD, and (B10.D2 x B10.G)F1 mice] with the peptide induced strong serum immunoglobulin G (IgG) responses to recombinant PAc (rPAc) and the peptide. Subcutaneous immunization of mice carrying the haplotype k or b of the H-2 I-A gene (C3H/HeN, C57BL/6, B10.BR, B10.A, or B10 mice) with the peptide induced intermediate serum IgG responses to rPAc and the peptide, and subcutaneous immunization of mice carrying the haplotype s or q of the H-2 I-A gene (DBA/1, B10.S, or B10.G mice) induced weak serum IgG responses to rPAc and the peptide compared with the responses of mice carrying the I-Ad gene. PAc(301-319) strongly induced PAc(301-319)-specific T-cell proliferation in B10.D2 mice but not in B10.G mice. The T-cell proliferation in B10.D2 mice was inhibited by treatment of antigen-presenting cells with anti-I-Ad monoclonal antibody but not with anti-I-Ab monoclonal antibody. These results indicate that the immune responses to the peptide in mice are genetically restricted or dominated by the MHC class II gene (I-Ad). To map antigenic epitopes in PAc(301-319) and PAc in mice bearing different H-2 haplotypes, 10 overlapping decapeptides covering PAc(301-319) and 153 decapeptides covering the entire mature PAc were synthesized. Of 10 decapeptides covering PAc(301-319), 6, 7, 1, and 1 decapeptides showed strong reactions with anti-PAc(301-319) sera from B10.D2 (H-2d), B10.GD (H-2g2), B10.BR (H-2k), and B10.A (H-2a) mice, respectively. None of these overlapping decapeptides reacted with anti-PAc(301-319) sera from B10.S (H-2s) and B10.G (H-2q) mice. Epitope-scanning analyses of the mature PAc molecule showed that antigenic epitopes scattered throughout the molecule and that antigenic epitope patterns differed in mice with different H-2 haplotypes. In addition, there was little overlap of immunogenic peptides among the mice with different haplotypes.

Immunogenetics and the major histocompatibility complex

The poultry immune system is a complex system involving many different cell types and soluble factors that must act in concert to give rise to an effective response to pathogenic challenge. The complexity of the immune system allows the opportunity for genetic regulation at many different levels. Cellular communication in the immune response, the production of soluble factors, and the rate of development of immune competency are all subject to genetic influences. The genes of the major histocompatibility complex (MHC) encode proteins which have a crucial role in the functioning of the immune system. The MHC antigens of chickens are cell surface glycoproteins of three different classes: Class I (B-F), Class II (B-L) and Class IV (B-G). The MHC antigens serve as essential elements in the regulation of cell-cell interactions. The MHC has been shown to influence immune response and resistance to autoimmune, viral, bacterial and parasitic disease in chickens. The MHC has been the primary set of genes identified with genetic control of immune response and disease resistance, but there are many lesser-characterized genes outside of the MHC that also regulate immunoresponsiveness. Polygenic control has been identified in selection experiments that have produced lines of chickens differing in antibody levels or kinetics of antibody production. These lines also differ in immunoresponsiveness and resistance to a variety of diseases. Understanding the genetic bases for differences in immunoresponsiveness allows the opportunity selectively to breed birds which are more resistant to disease. Indirect markers that can be used for this selection can include the MHC genes and immune response traits that have been associated with specific or general resistance to disease.

Genetic control of immune responsiveness to SCW

Genetic control of immune responsiveness to SCW

Genetic control of immune response and disease susceptibility by the HLA-DQ gene

The particular alleles of the HLA-DQ locus may control the low immune response to natural antigens by a dominant genetic trait through the immune suppression mediated by CD8 + suppressor T cells. The suppressor T cells may be activated by DQ-restricted and antigen-specific CD4 + suppressor/inducer T cells, because (1) a statistically significant association and linkage between low immune responsiveness to the natural antigens and the HLA-DQ gene were observed; (2) antigen-specific CD4 + T cells restricted by the DQ molecules encoded for by the HLA-DQ allele associated with low responsiveness were evidence in many low responders; and (3) anti-HLA-DQ mAb restored the immune response to natural antigens, in some low responders. This HLA-DQ-controlled polymorphism of immune response to the natural antigens may account for the association between HLA-DQ alleles and organ-specific autoimmune diseases.