Ovar-Mhc--ovine major histocompatibility complex: role in genetic resistance to diseases

Research on the structure of the ovine major histocompatibility complex (MHC), Ovar-Mhc, and its association with resistance to various diseases in sheep has received increasing attention during recent years. The term 'resistance' is used to denote the capacity of an animal to defend itself against disease or to withstand the effects of a harmful environmental agent. The Ovar-Mhc is poorly characterised when compared to MHCs of other domestic animals. However, its basic structure is similar to that of other animals, comprising Class I, II and III regions. Products of the Class I and II genes, the histocompatibility molecules, are of paramount importance as these present antigens to T-lymphocytes, thereby eliciting immune responses. Several studies have been conducted in sheep on the involvement of MHC genes/antigens in genetic resistance to diseases, the majority being concerned with gastrointestinal nematodes. Studies on resistance to footrot, Johne's disease and bovine leukaemia virus (BLV)-induced leukaemogenesis have also been reported. Genes of all three regions were implicated in the disease association studies. In addition to disease resistance, Ovar-Mhc genes have been found to be associated with traits such as marbling and birthweight. The use of genetic markers from within the Ovar-Mhc may be useful, via marker-assisted selection, for increasing resistance to various diseases provided they do not impact negatively on other economically-important traits. This review summarises current knowledge of the role of Ovar-Mhc in genetic resistance to diseases in sheep.     

Genetic control of immunity to Eimeria tenella. Interaction of MHC genes and non-MHC linked genes influences levels of disease susceptibility in chickens

The relative importance of MHC genes and background genes in the genetic control of disease susceptibility and the development of protective immunity to E. tenella infection was investigated in eight different strains of 15I5-B congenic and four inbred chicken strains. RPRL 15I5-B congenic chickens that share a common genetic background but express different B haplotypes demonstrated wide variations in disease susceptibility and the development of acquired resistance to E. tenella infection. Infection of chickens sharing a common B haplotype but expressing different genetic backgrounds showed quite contrasting levels of susceptibility to secondary E. tenella infection. In all chicken strains examined, infected chickens developed high levels of serum and biliary anti-coccidial antibodies regardless of their B haplotypes. Furthermore, no correlation between antibody levels and the phenotypically expressed levels of disease resistance was demonstrated. These findings lend support to the view that interaction of MHC genes and non-MHC genes influences the outcome of host response to E. tenella infection.     

Future applications of biotechnology in poultry

The major biotechnological advances that can be applied in the poultry industry will include molecular genetics, molecular immunology, and solid-state reactions. The elucidation of the genetic code and the development of techniques to manipulate genes offer new opportunities for changing pathogenic agents and changing chickens to reduce the effect of disease and improve productivity. The monoclonal antibody technique and the discovery that cells of the immune response communicate with one another through peptide factors will permit improved diagnostic techniques and enhanced immune responses to vaccines. Immunologic and biochemical reactions that occur on a solid substrate can be used to simplify and accelerate diagnostic tests and to purify antigens and antibodies. These advances will lead to improvements in diagnosis, disease resistance, and productivity of poultry.     

Structure and function of the major histocompatibility complex in domestic animals

The major histocompatibility complex (MHC) is a genetic region that has been intensively studied for the past 2 decades. Interest in the MHC has been high because of (i) the particular involvement of the MHC in transplantation reactions, including organ allograft rejection in human beings; and (ii) the more general role of MHC gene products in the genetic control of immune responses in all mammals. The MHC has several remarkable properties that include a distinctive genetic structure which has been well-preserved through evolution, and the extreme plasticity of form of the principal MHC genes, which can coexist within a single species in 30 or more allelic forms. The genes of the MHC regulate cell-cell interactions of various types within the lymphoreticular system, and thus function as the so-called "immune response" genes that have been described in mice, rats, and guinea pigs. In human beings, the "disease associations" demonstrated between MHC alleles and various pathologic conditions are probably manifestations of abnormal functions of immune regulation governed by the MHC. Studies of the MHC in domestic species are still in their infancy. However, investigations of the MHC have been carried out in swine, cattle, horses, sheep, goats, dogs, and chickens. Further research on the MHC of domestic animals is merited, both for its contribution to the overall understanding of the biological significance of the MHC and for its practical application in clinical veterinary medicine.     

Immunological basis of differences in disease resistance in the chicken

Genetic resistance to diseases is a multigenic trait governed mainly by the immune system and its interactions with many physiologic and environmental factors. In the adaptive immunity, T cell and B cell responses, the specific recognition of antigens and interactions between antigen presenting cells, T cells and B cells are crucial. It occurs through a network of mediator proteins such as the molecules of the major histocompatibility complex (MHC), T cell receptors, immunoglobulins and secreted proteins such as the cytokines and antibodies. The diversity of these proteins that mainly is due to an intrinsic polymorphism of the genes causes phenotypic variation in disease resistance. The well-known linkage of MHC polymorphism and Marek's disease resistance difference represents a classic model revealing immunological factors in resistance differences and diversity of mediator molecules. The molecular bases in any resistance variation to infectious pathogens are vaguely understood. This paper presents a review of the major immune mediators involved in resistance and susceptibility to infectious diseases and their functional mechanisms in the chicken. The genetic interaction of disease resistance with production traits and the environment is mentioned.     

Expression kinetics of chicken β2-microglobulin and Class I MHC in vitro and in vivo during Marek’s disease viral infections

Marek’s disease virus (MDV) is a highly cell-associated herpesvirus that causes a disease in chickens characterized by tumor formation and immunosuppression. The changes of major histocompatibility complex (MHC) expression in different MDV-infected cells are not completely understood. In this study, we investigated the expression of the Class I MHC and β2-microglobulin (β2m) genes in response to MDV infection at different time points by real-time PCR. In both in vitro and in vivo, the expression levels of Class I MHC and β2m genes were upregulated during early MDV infections in comparison to control cells; We also found that the expression of Class I MHC gene was downregulated in BudR (5-bromo-2′-deoxyuridine)-treated MSB1 cells at 48 h and MDV-infected chicken embryo fibroblast cells (CEF) at 120 and 168 h post infection (hpi); Furthermore, compared to control groups, Class I MHC and β2m expression levels were downregulated in peripheral blood lymphocytes (PBLC) from MDV-infected chickens at 14 and 28 days post infection (dpi); Interestingly, both Class I MHC and β2m gene expression levels increased again in PBLC from MDV RB1B-infected chickens at 35 dpi, in which MDV was in the latent or transformed infection stages. In addition, Class I MHC expression was clearly decreased in MDV-infected CEF at 120 hpi although β2m expression was significantly increased. These changes in Class I MHC and β2m gene expression might provide more insights into host-virus interaction.     

Major histocompatibility complex locus DRA polymorphism in the endangered Sorraia horse and related breeds

The major histocompatibility complex (MHC) genes play well‐defined roles in eliciting immune responses and combating infectious diseases. This genetic system is among the most polymorphic. The extent of genetic variation within a population has been directly correlated with fitness for many traits. The MHC class II locus DRA polymorphism was analysed in the endangered Sorraia horse, two other Portuguese and four New World horse breeds considered to be historically close to the Sorraia. Comparison of the Sorraia with other breeds demonstrated less MHC variation among Sorraia horses. If DRA polymorphism provides greater disease resistance, selective breeding to increase MHC polymorphism may increase fitness of this population.     

Immune modulation: the genetic approach

As part of a comprehensive strategy to combat diseases, improving genetically resistance to diseases and therefore immune capacities of animals is more and more desirable. However, research is still needed to develop genetic tools that may be used. In this search, lines selected for various immune responses are used to study relevant immune markers. Chickens have been selected for six generations for three different in vivo immune responses: high antibody response, high cell-mediated immune response and high phagocytic activity. Each line, selected for one trait, showed significant increase in immune capacity for this trait. In addition, results showed clearly independence between the three immune responses analyzed, meaning that a global approach is needed to improve immune capacity. Selected lines allow to follow genetic markers linked to immune response genes. In the different lines, different patterns in MHC gene frequency were observed and MHC alleles differed in their effects according to the immune trait. Some correlations were found between immune responses and production traits. The selected lines will be used to find other "known" immune response genes or "anonymous" genetic markers, which may become the future tools to modulate immune responsiveness of animals.     

Genetic variation and responses to vaccines

Disease is a major source of economic loss to the livestock industry. Understanding the role of genetic factors in immune responsiveness and disease resistance should provide new approaches to the control of disease through development of safe synthetic subunit vaccines and breeding for disease resistance. The major histocompatibility complex (MHC) has been an important candidate locus for immune responsiveness studies. However, it is clear that other loci play an important role. Identifying these and quantifying the relative importance of MHC and non-MHC genes should result in new insights into host-pathogen interactions, and information that can be exploited by vaccine designers. The rapidly increasing information available about the bovine genome and the identification of polymorphisms in immune-related genes will offer potential candidates that control immune responses to vaccines. The bovine MHC, BoLA, encodes two distinct isotypes of class II molecules, DR and DQ, and in about half the common haplotypes the DQ genes are duplicated and expressed. DQ molecules are composed of two polymorphic chains whereas DR consists of one polymorphic and one non-polymorphic chain. Although, it is clear that MHC polymorphism is related to immune responsiveness, it is less clear how different allelic and locus products influence the outcome of an immune response in terms of generating protective immunity in outbred animals. A peptide derived from foot-and-mouth disease virus (FMDV) was used as a probe for BoLA class II function. Both DR and DQ are involved in antigen presentation. In an analysis of T-cell clones specific for the peptide, distinct biases to particular restriction elements were observed. In addition inter-haplotype pairings of DQA and DQB molecules produced functional molecules, which greatly increases the numbers of possible restriction elements, compared with the number of genes, particularly in cattle with duplicated DQ genes. In a vaccine trial with several peptides derived from FMDV, BoLA class II DRB3 polymorphisms were correlated with both protection and non-protection. Although variation in immune responsiveness to the FMDV peptide between different individuals is partly explainable by BoLA class II alleles, other genetic factors play an important role. In a quantitative trait locus project, employing a second-generation cross between Charolais and Holstein cattle, significant sire and breed effects were also observed in T-cell, cytokine and antibody responses to the FMDV peptide. These results suggest that both MHC and non-MHC genes play a role in regulating bovine immune traits of relevance to vaccine design. Identifying these genes and quantifying their relative contributions is the subject of further studies.     

Immune responses against Marek's disease virus

It is more than a century since Marek's disease (MD) was first reported in chickens and since then there have been concerted efforts to better understand this disease, its causative agent and various approaches for control of this disease. Recently, there have been several outbreaks of the disease in various regions, due to the evolving nature of MD virus (MDV), which necessitates the implementation of improved prophylactic approaches. It is therefore essential to better understand the interactions between chickens and the virus. The chicken immune system is directly involved in controlling the entry and the spread of the virus. It employs two distinct but interrelated mechanisms to tackle viral invasion. Innate defense mechanisms comprise secretion of soluble factors as well as cells such as macrophages and natural killer cells as the first line of defense. These innate responses provide the adaptive arm of the immune system including antibody- and cell-mediated immune responses to be tailored more specifically against MDV. In addition to the immune system, genetic and epigenetic mechanisms contribute to the outcome of MDV infection in chickens. This review discusses our current understanding of immune responses elicited against MDV and genetic factors that contribute to the nature of the response.     

The antibody repertoire in infection and vaccination with Dictyocaulus viviparus: heterogeneity in infected cattle and genetic control in guinea pigs.

The antigen recognition profiles of serum antibody from calves infected or vaccinated with irradiated Dictyocaulus viviparus larvae were analysed by immunoprecipitation of radio-iodinated in vitro-released excretory-secretory materials from live adult parasites. Immunoprecipitates were analysed by SDS-PAGE and considerable heterogeneity in antigen recognition between individual animals was observed, regardless of infection regimen. This heterogeneity was also found to occur amongst outbred guinea pigs infected with the parasite and permitted an examination of the genetics of the effect using inbred guinea pigs (Strains 2 and 13). The antibody repertoires of the two strains were distinct, with only slight variation occurring between individuals within a strain. Previous work on nematode infections in rodents has demonstrated a role for the major histocompatibility complex (MHC) in the control of the immune repertoire. If this, as is probable, holds for the guinea pig, then it can be ascribed to the MHC Class II region because Strain 2 and Strain 13 bear identical Class I alleles but disparate Class II alleles. Whilst there is no evidence to date that the efficiency of vaccination of cattle is influenced by genetic factors, the operation of vaccines based on a single or a few molecularly cloned parasite antigens might be seriously compromised by the kind of genetic restriction to the immune repertoire described here.     

Genetic characterisation of protective vaccine responses in sheep using multi-valent Dichelobacter nodosus vaccines

Protective vaccine responses to nine distinct serogroups of Dichelobacter nodosus (serogroups A-I) can be readily measured by serogroup-specific K-agglutinating antibody titres. On the basis of a large quantitative genetic experiment (1200 progeny from 129 sire groups), it was shown that variation in antibody responses following vaccination with a multi-valent pilus antigen D. nodosus vaccine (serogroups A-I) is, in part, under genetic control and thus heritable. Based on the genetic relationships between antibody responses to all nine antigens, results suggested that both genes for a broad-based and genes for serogroup-specific response contributed to genetic variation in vaccine response. Furthermore, preliminary data in 389 progeny showed that polymorphism within the ovine major histocompatibility (MHC) based on serological classification accounted for a significant proportion of the variation in vaccine responses. In subsequent experimentation, we examined the importance of genetic polymorphism within the ovine MHC, and the possibility of genes outside the MHC for their involvement in antigen-specific and broad-based vaccine response. Within two large half sib families(131, and 143 progeny), four MHC haplotypes were investigated and found to be associated with differential antibody responses to six out of eight distinct vaccine-antigens presented to the host in a multi-valent vaccine. The model used here shows how well characterised immunogens, quantitative genetic experimentation, and molecular gene mapping tools can be used to unravel genetic differences in host responses to commercial vaccines.     

Genetic control of disease resistance and immunoresponsiveness.

A great deal of evidence points to substantial genetic control over at least some of the immune responses, although genetic parameters for clinical disease have been less favorable. The past two decades have illustrated that single genes with a large impact on food animal health do exist and can be used to improve the health of domestic populations. The current focus on molecular genetics within food animal species will likely unveil numerous other examples of single genes with large effects, although the use of animals possessing favorable genotypes for disease resistance may represent a compromise in selection for increased production of raw product. Moreover, it is also clear that genetic control over the immune system is not limited to a few genes but is more likely influenced by many genes, each with small effects. The use of this information in animal improvement programs is not straightforward because of factors complicating the identification of superior individuals within the population. The scarcity of information dealing with phenotypic and genetic relationships between measures of disease resistance and aspects of immune response complicates the situation even further. Despite these potential hurdles, the potential for permanent improvement of disease resistance within food animal species in the future is tantalizing and merits intensified future study.     

Environment-genetic influences on immunocompetence

The immunological responses of an animal are changing continually in response to perceived environmental changes. This is because the genetic background, the lifelong environment of animals and their interaction greatly influence immunological responsiveness. An animal's genetic background influences all factors related to immunocompetence. Among these are age of onset of immunocompetence, responsiveness to specific antigens, antibody titers, type of antibody and immune response, as well as the persistence of the responses. Defense by immunity must require considerable resources, because chickens with a high antibody response are smaller and have poorer feed efficiencies than those chickens whose antibody response is lower. An increase in the effectiveness of one defensive factor may result in reduced effectiveness of another factor. For example, chickens selected for a high antibody titer response to antigen have reduced effectiveness of macrophages. Environmental stresses influence the immune response. Stress at the time of the animal's contact with antigen results in a reduced antibody response. After the antibody response begins, stress has little effect. Stress promotes the sensitization of cell-mediated immunity but inhibits its effectiveness. A short-term stressor such as weaning is followed, in about 24 h, by a short period of reduced immunocompetence, even though lymphoid mass may be reduced. Reduced immunocompetence during stressful periods can be reduced by employing adrenal blocking chemicals, or by socializing animals to their handlers.     

Response of three class‐IV major histocompatability complex haplotypes to Eimeria acervulina in meat‐type chickens

1. The importance of MHC genes and background genes in controlling disease resistance, including resistance to avian coccidiosis, has not been clarified in meat‐type chickens.

2. The role of class IV MHC genes in resistance to Eimeria acervulina was assessed in F2 progeny of a cross between 2 meat‐type lines, selected divergently for immune response to Escherichia coli.

3. Disease susceptibility was assessed by lesion score, body weight, packed cell volume and carotene absorption.

4. Chickens with the “K” class IV MHC haplotype had lower lesion scores than chickens with “F” and “A” haplotypes.

5. Plasma carotene concentrations were higher in chickens with “K” haplotype and lower in chickens with “F” and “A” haplotypes whereas body weight and packed cell volume were less sensitive measures of Eimeria infection.

6. Eimeria acervulina resistance appears to be associated with MHC class IV genes; information about MHC haplotypes may be useful in selecting for increased resistance of meat‐type chickens to coccidiosis.     

Study of host-pathogen interactions to identify sustainable vaccine strategies to Marek's disease

Marek’s disease virus is a highly cell-associated, lymphotropic -herpesvirus that causes paralysis and neoplastic disease in chickens. The disease has been contained by vaccination with attenuated viruses and provides the first evidence for a malignant cancer being controlled by an antiviral vaccine. Marek’s disease pathogenesis is complex, involving cytolytic and latent infection of lymphoid cells and oncogenic transformation of CD4⁺ T cells in susceptible chickens. Innate and adaptive immune responses develop in response to infection, but infection of lymphocytes results in immunosuppressive effects. The remarkable ability of MDV to escape immune responses by interacting with, and down-regulating, some key aspects of the immune system will be discussed in the context of genetic resistance. Resistance conferred by vaccination and the implications of targeting replicative stages of the virus will also be examined.     

Genetic variations in the antibody response in young bulls

Considerable evidence for the existence of a direct genetic control of the immune response has been presented during recent years. Experimental work with rodents are the main basis for this evidence. The first study on genetic variations in the antibody response was carried out by Gorer & Schütze (1938). Later Cinader (1960) published detailed considerations about the specificity and inheritance of the antibody response. In mice it has been demonstrated that a few dominant immune response (Ir) genes determine the ability to produce antibodies against certain specific antigens (McDevitt & Tyan 1968). The magnitude of the response is probably under the influence of polygenes, which are not associated with Ir genes. This theory is supported by selection for high and low antibody production in mice (Biozzi et al. 1972).     

In vivo administration of ligands for chicken toll-like receptors 4 and 21 induces the expression of immune system genes in the spleen

Toll-like receptors (TLRs) are a group of conserved proteins that play an important role in pathogen recognition in addition to the initiation and regulation of innate and adaptive immune responses. To date, several TLRs have been identified in chickens, each recognizing different ligands. TLR stimulation in chickens has been shown to play a role in host-responses to pathogens. However, the mechanisms through which TLRs modulate the chicken immune system have not been well examined. The present study was conducted to characterize the kinetics of responses to TLR4 and TLR21 stimulation in chickens following intramuscular injections of their corresponding ligands, lipopolysaccharide (LPS) and CpG oligodeoxynucleotides (ODNs), respectively. To this end, relative expression of cytokine genes in the spleen was determined at 2, 6, 12 and 24 h after injection of TLR ligands. The results indicated that LPS strongly induced the up-regulation of some immune system genes early on in the response to treatment, including interferon (IFN)-γ, interleukin (IL)-10, and IL-1β. Furthermore, treatment with CpG ODN promoted the up-regulation of major histocompatibility complex (MHC)-II, IFN-γ and IL-10. The response to CpG ODN appeared to be somewhat delayed compared to the response to LPS. Moreover, we found a significant increase in IFN-α gene expression in response to LPS but not CpG ODNs. Future studies may be aimed to further characterize the molecular mechanisms of TLR activation in chickens or to exploit TLR agonists as vaccine adjuvants.     

Genetic control of immune responsiveness: a review of its use as a tool for selection for disease resistance

Disease resistance and immune responsiveness have been traits generally ignored by animal breeders. Recent advances in immunology and molecular biology have opened new avenues towards our understanding of genetic control of these traits. The major histocompatibility gene complex (MHC) appears to play a central role in all immune functions and disease resistance. The need to understand the relationship between immune responsiveness, disease resistance and production traits is discussed in this review. Antagonistic relationships might prevent simultaneous improvement of all of these traits by conventional breeding methods. It is suggested that genetic engineering methods may allow the simultaneous improvement of disease resistance and production traits in domestic animals. Genes of the MHC will be especially good candidates for genetic engineering experiments to improve domestic species.     

Escherichia coli challenge in chickens selected for high or low antibody response and differing in haplotypes at the major histocompatibility complex.

Relative sensitivity to Escherichia coli challenge was evaluated in white leg-horn chickens that had been selected for high antibody (HA) or low antibody (LA) response and that differed in haplotypes at the major histocompatibility complex (MHC). Assessments were made of relative body-weight change and of heart and air-sac lesions after inoculation of 10(6), 10(5), or 10(4) E. coli via the posterior thoracic air sac. As has previously been reported, chicks from line HA were more sensitive to E. coli than those from line LA. Lesion scores were 1.58 +/- 0.12 in line HA and 1.02 +/- 0.12 in line LA (mean +/- S.E.), and ranged from 0.99 +/- 0.14 with the lowest dose of E. coli to 1.79 +/- 0.15 for the highest dose. Relative body-weight change to 72 hours after inoculation was greater in line LA (7.5 +/- 0.5) than in line HA (4.4 +/- 0.8). There was no apparent resistance or susceptibility conferred to chickens in either the HA or LA genetic background as a result of haplotypes present at the MHC.