New allele frequency database: http://www.allelefrequencies.net

A new website (http://www.allelefrequencies.net) has been compiled to execute the frequency of alleles at various polymorphic regions of different populations in the field of histocompatibility and immunogenetics. Data for HLA alleles has been added but this will be extended to include frequency data of polymorphisms in other immunogenetic regions, e.g. cytokines, KIR receptors, MIC.     

Cutting Edge Issues in Autoimmune Gastritis

Autoimmune gastritis is the outcome of a pathological CD4 T cell-mediated autoimmune response directed against the gastric H/K-ATPase. Silent initially, the gastric lesion becomes manifest in humans by the development of megaloblastic pernicious anemia arising from vitamin B12 deficiency. Cutting edge issues in this disease relate to its epidemiology, immunogenetics, a role for Helicobacter pylori as an infective trigger through molecular mimicry, its immunopathogenesis, associated organ-specific autoimmune diseases, laboratory diagnosis, and approaches to curative therapy.     

THE GUINEA-PIG I-REGION: III. DISTRIBUTION OF Ia ANTIGENS IN INBRED AND PARTIALLY INBRED STRAINS

We have used a combined serologic and structural approach to study the distribution of I-region associated (Ia) antigens in nine strains of inbred and partially inbred guinea-pigs. All of the inbred strains studied with the exception of strain 2 animals were found to share one or more I-subregions with inbred strain 13 animals. The BIOAD, R9, OM3, and BIOAC strains have the same I-region as strain 13 animals; the B/Lac strain has two subregions in common with strain 13, while the BIOB strain has a single subregion in common with strain 13. The availability of a number of different guinea-pig strains with well characterized major histocompatibility complexes should facilitate the continuing use of this species in studies of immunogenetics, transplantation, and tumour immunology.     

The polymerase chain reaction for detection of T-cell antigen receptor expression.

Applications of the polymerase chain reaction have revolutionized the field of immunogenetics, particularly in studies of human leukocyte antigen class II polymorphism, and more recently in the analysis of T-cell receptor usage. However, the enormous diversity and variability of the T-cell receptor complex have made the amplification of the complete repertoire difficult. Several methods have been devised to address this problem. Each system is described with recent examples of its use and an assessment of its advantages and disadvantages. The use of quantitative polymerase chain reaction in T-cell receptor analysis is also discussed. The elucidation of the T-cell repertoire involved in a pathogenic process can have therapeutic implications, given the success of reversing experimental autoimmune disorders by directing specific forms of immunotherapy against V region gene products.     

THE USE OF EARLY EMBRYO AGGREGATION DERIVED MOUSE CHIMAERAS. II. THE STUDY OF DISEASE PROCESSES*

Early embryo aggregation derived mouse chimaeras have proven an extremely valuable tool to study development of disease processes. In this respect chimaeras prove a unique opportunity to study the interaction between cells genetically predestined to become diseased and a normal cell population within the same animal. In this situation chimaeras can be studied in view of possible ‘correction’ of the disease by the provision of a population of normal host cells and/or their products. Various host deficiency states including classic immune deficiency, potentially ‘deficient’ anaemias and tumours have been studied–the subject of the review here.     

Role of bacterial products in periodontitis: immune response in gnotobiotic rats monoinfected with Eikenella corrodens.

The development of humoral and cell-mediated immune responses to Eikenella corrodens (a bacterium that causes periodontal lesions in gnotobiotic rats) was measured and compared with the rate of appearance of macroscopic lesions. A possible inverse relationship was found. A strong cell-mediated immune response, as measured by skin reactivity and lymphocyte mitogenesis, occurred between 4 and 6 weeks after infection and subsided soon thereafter to a low response level. Humoral antibodies to endotoxin from E. corrodens could not be detected at any time. The disease developed only after the cell-mediated immune response diminished, thus suggesting that lack of an efficient immune response may permit the development of the disease. This is seemingly in contradiction to the assumption that tissue destruction in such cases is caused by the immune response and its products. We are inclined to believe, based on our findings reported here, that the lack of immune responsiveness to the bacterium and/or its products is the major causative factor in the development of periodontitis. At the same time, we wish to emphasize that occurrence of both phenomena during the long development of periodontal disease is possible.     

Multiple sclerosis: immunologic aspects.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS). Although the causes are not known, the pathogenesis likely involves complex relationships between autoimmunity, immunogenetics, immunologic deficiency and viral infection. The evidence for such interrelationships is discussed.     

The guinea-pig I-region. III. Distribution of Ia antigens in inbred and partially inbred strains

We have used a combined serologic and structural approach to study the distribution of I-region associated (Ia) antigens in nine strains of inbred and partially inbred guinea-pigs. All of the inbred strains studied with the exception of strain 2 animals were found to share one or more I-subregions with inbred strain 13 animals. The BIOAD, R9, OM3, and BIOAC strains have the same I-region as strain 13 animals; the B/Lac strain has two subregions in common with strain 13, while the BIOB strain has a single subregion in common with strain 13. The availability of a number of different guinea-pig strains with well-characterized major histocompatibility complexes should facilitate the continuing use of this species in studies of immunogenetics, transplantation, and tumour immunology.     

Primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a fibrosing disease of the intra- and extra-hepatic bile ducts, and is closely associated with inflammatory bowel disease. It is immune mediated, rather than being a classical autoimmune disease. A range of immune abnormalities have been demonstrated in PSC, in particular the findings of a range of autoantibodies, a portal tract infiltrate of functional T cells, a restricted T-cell receptor repertoire, and aberrant expression of HLA molecules on biliary epithelial cells. The immunogenetics of PSC is currently under study and to date 4 key HLA haplotypes associated with PSC have been developed. The trigger factor for the initiation of the immune response may be the ingress of bacteria or other toxic metabolites into the portal circulation through a diseased and permeable bowel wall.     

Physiological aspects of exocytosis in chromaffin cells of the adrenal medulla

The adrenal medulla is composed principally of groups of adrenergic and noradrenergic chromaffin cells, with minor populations of small intensely fluorescent cells and ganglionic neurones. Different molecular stimuli evoke distinct secretory events in the gland, involving the release of either adrenaline or noradrenaline together with various neuroactive peptides. The nature of the secretory response can be controlled at a central level or regulated locally within the gland. Specific innervation patterns to the different types of chromaffin cell have been implicated in central regulatory mechanisms, while several explanations for regulating secretion locally have been proposed. The differential distribution of various types of receptors between cell phenotypes, such as muscarinic or nicotinic acetylcholine receptors, histamine receptors, angiotensin receptors and different classes of opiate receptors between the two principal chromaffin cell populations could be involved in local control. In addition exocytosis parameters could be modulated differently in adrenergic and noradrenergic cells by phenotype-specific mechanisms, possibly involving molecules like Growth Associated Protein-43, Synaptosomal Associated Protein-25 isoforms or the p11 annexin subunit. The distribution of the various types of calcium channels is also known to vary between chromaffin cell subtypes. This short review examines possible ways in which specific innervation patterns in the adrenal gland could be programmed and discusses exocytosis mechanisms that could differ between chromaffin cell phenotypes. Data reviewed here suggest that the adrenal medulla should no longer be viewed as a homogeneous entity but as consisting of an ensemble of individual cell subpopulations each with a distinct secretory response that could in part reflect its local history.     

Understanding inflammatory bowel disease via immunogenetics

The major inflammatory bowel diseases, Crohn's disease and ulcerative colitis, are both debilitating disorders of the gastrointestinal tract, characterized by a dysregulated immune response to unknown environmental triggers. Both disorders have an important and overlapping genetic component, and much progress has been made in the last 20 years at elucidating some of the specific factors contributing to disease pathogenesis. Here we review our growing understanding of the immunogenetics of inflammatory bowel disease, from the twin studies that first implicated a role for the genome in disease susceptibility to the latest genome-wide association studies that have identified hundreds of associated loci. We consider the insight this offers into the biological mechanisms of the inflammatory bowel diseases, such as autophagy, barrier defence and T-cell differentiation signalling. We reflect on these findings in the context of other immune-related disorders, both common and rare. These observations include links both obvious, such as to pediatric colitis, and more surprising, such as to leprosy. As a changing picture of the underlying genetic architecture emerges, we turn to future directions for the study of complex human diseases such as these, including the use of next generation sequencing technologies for the identification of rarer risk alleles, and potential approaches for narrowing down associated loci to casual variants. We consider the implications of this work for translation into clinical practice, for example via early therapeutic hypotheses arising from our improved understanding of the biology of inflammatory bowel disease. Finally, we present potential opportunities to better understand environmental risk factors, such as the human microbiota in the context of immunogenetics.     

The multifaceted murine plasmacytoid dendritic cell

Plasmacytoid dendritic cells (PDCs) or natural interferon-producing cells, function as the body’s innate defense against viral infections. As discussed here, they may play additional roles in response to bacterial pathogens and may have the capacity to induce different type of T-cell responses depending on what signals they receive. The discovery of murine PDCs will allow for the design of models to study viral immunobiology in vivo and to determine their function in various diseases that involve plasmacytoid dendritic cells, such as selected leukemias, lymphomas, allergies, different autoimmune conditions, and their possible role in inducing and maintaining tolerance.     

Non-HLA immunogenetics in hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) provides a unique environment in which to evaluate the role of immunogenetics of both the donor and the recipient to success of the procedure. The central role of HLA matching in HSCT has been established; however, recipients of allogeneic HSCT incur the risk of graft versus host disease (GVHD) even when the donor is a sibling who shares the major histocompatibility genes. Therefore, the perfect HLA match does not represent the optimal genetic make up. Other genetic systems operate and affect the various outcomes of HSCT, including GVHD, infections, transplant-related mortality, and overall survival. Minor histocompatibility antigens contribute to the control of GVHD as well as graft versus leukaemia reactions. In addition, genes controlling inflammatory processes, including cytokines, chemokines and their receptors, can modulate GVHD, and genes from both arms of the immune response (innate and adaptive) are strong candidates for susceptibility factors to infections in allogenic transplantation.     

Immunopathogenesis of primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology; however, lymphocytic portal tract infiltration is suggestive of an immune-mediated basis for PSC. Associations with inflammatory bowel disease— especially ulcerative colitis—and with other auto-immune diseases, together with genetic associations, further suggest that PSC may be an immune-mediated disease. The immunogenetics of PSC have been the subject of active research, and several human leukocyte antigen (HLA)- and non-HLA-associated genes have been implicated in the development of the disease. Lymphocytes derived from the inflamed gut may enter the liver via the enterohepatic circulation to cause hepatic disease. PSC may be triggered in genetically susceptible individuals by infections or toxins entering the portal circulation through a permeable colon and, therefore, evoking an abnormal immune response.     

A long road/read to rapid high-resolution HLA typing: The nanopore perspective

Next-generation sequencing (NGS) has been widely adopted for clinical HLA typing and advanced immunogenetics researches. Current methodologies still face challenges in resolving cis–trans ambiguity involving distant variant positions, and the turnaround time is affected by testing volume and batching. Nanopore sequencing may become a promising addition to the existing options for HLA typing. The technology delivered by the MinION sequencer of Oxford Nanopore Technologies (ONT) can record the ionic current changes during the translocation of DNA/RNA strands through transmembrane pores and translate the signals to sequence reads. It features simple and flexible library preparations, long sequencing reads, portable and affordable sequencing devices, and rapid, real-time sequencing. However, the error rate of the sequencing reads is high and remains a hurdle for its broad application. This review article will provide a brief overview of this technology and then focus on the opportunities and challenges of using nanopore sequencing for high-resolution HLA typing and immunogenetics research.     

HLA-B*35-Restricted CD8+-T-Cell Epitope in Mycobacterium tuberculosis Rv2903c

Few human CD8(+) T-cell epitopes in mycobacterial antigens have been described to date. Here we have identified a novel HLA-B*35-restricted CD8(+) T-cell epitope in Mycobacterium tuberculosis Rv2903c based on a reverse immunogenetics approach. Peptide-specific CD8 T cells were able to kill M. tuberculosis-infected macrophages and produce gamma interferon and tumor necrosis factor alpha.     

The regulation and expression of MHC class I genes.

The expression of mouse MHC class I genes and their products in vivo reveals complex patterns of regulation. Different promoter elements, which are required for gene activation or modulation in response to various external stimuli, have now been characterized as well as the proteins that bind to them. As described here by Brigitte David-Watine and colleagues, the picture that has gradually emerged from these in vitro studies is of an intricate interplay of transacting factors that ultimately lead to the fine tuning of MHC class I expression in vivo.     

IMMUNOGENETIC ANALYSIS OF HLA-DR10 HOMOZYGOUS INDIVIDUALS

Molecular, cellular and serological analysis of Major Histocompatibility Complex alleles was performed on three individuals who appeared to be HLA-DR10 homozygous by DNA restriction fragment analysis. Each donor was of different ethnic origin: Caucasoid, Asian Indian and African Negroid. The results of our studies show that the Caucasoid and Asian donors are indeed homozygous for the HLA-DR 10 allele, while the African donor also possesses the DRB1*0103 allele. Homozygosity for the HLA-A1B37-Cw6-DR10-DQ5 haplotype in the Caucasoid donor was confirmed by familial segregation analysis. The B-lymphoblastoid cell line produced from this donor should prove useful in studies of HLA immunogenetics.     

Role of arginine metabolism in immunity and immunopathology

A heterogeneous set of cells that are commonly grouped as "myeloid cells", interacts in a complex landscape of physiological and pathological situations. In this review we attempt to trace a profile of the "myeloid connection" through different normal and pathological states, by analyzing common metabolic pathways of the amino acid l-arginine. Myeloid cells exert various, often divergent, actions on the immune response through mechanisms that exploit mediators of this peculiar metabolic pathway, ranging from l-arginine itself to its downstream metabolites, like nitric oxide and polyamines. Various pathological situations, including neoplastic and autoimmune diseases, as well as injury repair and infections are discussed here, showing how l-arginine metabolism is able to play a dual role, both as an active protector and a possible threat to the organism.     

Listeria cell wall fraction. Characterization of in vitro adjuvant activity.

We have previously described a crude cell wall fraction of Listeria monocytogenes (LCWF) which induces resistance to listeria infection in mice, is a murine B-cell mitogen and is an immunological adjuvant. Data reported here show that LCWF, which is effective over a wide dose range, exerts its adjuvant action on early events in the induction of an immune response. Moreover, LCWF stimulates nonadherent cells to respond to sheep red cells when adherent cells are severely depleted or absent, suggesting that LCWF can therefore act directly on lymphocytes present within the non-adherent population.