Nomenclature for factors of the swine leukocyte antigen class II system, 2005

A systematic nomenclature for the genes and alleles of the swine major histocompatibility complex (MHC) is essential to the development and communication of research in swine immunology. The Swine Leukocyte Antigen (SLA) Nomenclature Committee of the International Society for Animal Genetics (ISAG) has reviewed all of the DNA-sequence information for MHC class II genes, available in GenBank/EMBL/DDBJ databases, and the associated published reports to develop such a systematic nomenclature. This article summarizes the proposed nomenclature, which parallels the World Health Organization's nomenclature for factors of the human MHC. The SLA class II genes expressed on the cell membrane will be noted as SLA-DRA, SLA-DRB1, SLA-DQA, and SLA-DQB1. Nomenclature assignments for all SLA class II GenBank sequences are now noted. The committee will add new SLA class II allele designations, as they are discovered, and will maintain a publicly available list of all recognized genes and alleles using the Immuno Polymorphism Database (IPD). The sequences will be available from the IPD-MHC section of the database which contains non-human MHC sequences (http://www.ebi.ac.uk/ipd/mhc/sla/).     

Echinococcosis and allergy

The larval stages of Echinococcus granulosus and E. multilocularis are involved in parasitic diseases in humans: cystic echinococcosis (CE) ("hydatid disease") and alveolar echinococcosis (AE), respectively. Both diseases and parasites have tight links with allergy because of the immunological characteristics that contribute to maintain the larvae in their human host as well as their potential in inducing clinical anaphylactic reactions in some patients. Clinical observations in patients and data obtained from mass screenings in various countries have identified both forms of echinococcosis as "polar diseases," i.e., diseases where immunological background of the patients was related to the clinical presentation and course. In particular, abortive cases (i.e., spontaneous cures) have been found in many subjects in endemic areas. On the other hand, immune suppression was associated with severe disease. AE especially might be considered as an opportunistic infection. Experimental and clinical studies have shown that Th1-related immune response was associated with protection and Th2-related response was associated with parasite growth. Genetic characteristics of the host are related to both occurrence and severity of AE and are associated with the extent of IL-10 secretion, which is a major feature of chronic progressing echinococcosis. Anaphylactic reactions, including urticaria, edema, respiratory symptoms, and anaphylactic shock due to spontaneous or provoked rupture of the parasitic cyst, are well known in CE. Anaphylactic reactions in AE are far less frequent, and have been observed in rare cases at time of metastatic dissemination of the parasitic lesions. Echinococcus-specific IgE is present in most of the patients and associated with severity. Specific histamine release by circulating basophils stimulated with E. granulosus antigens is present in all patients with CE and AE. Echinococcus allergens include (1) AgB 12-kDa subunit, a protease inhibitor and a potent Th2 inducer; (2) Ag5, a serine protease; (3) EA 21, a specific cyclophilin, with a homology with other types of cyclophilins; (4) Eg EF-1 beta/delta an elongation factor, with a homology with Strongyloides stercoralis EF that shares the same IgE epitope. A clinical cross-reaction with Thiomucase, a mucopolysaccharidase used in arthritis treatment, has recently been published. However, despite the potential risk of allergic reactions, the dogma "never puncture a hydatid cyst" is no longer valid. International experience of therapeutic technique of "puncture, aspiration, injection, re-aspiration" of hydatid cysts developed at the beginning of the 1980s has proved to be successful in a variety of selected indications that have been reviewed by WHO recommendations. A better understanding of the immunological background of echinococcosis in humans has led to new therapeutic developments, such as immunomodulation using interferon alpha. Th2-driven immunological response and IL-10-related tolerance state are common characteristics of atopic allergy and echinococcosis. The example of echinococcosis stresses the ambiguous links that exist between parasitic and allergic diseases, and show the usefulness of comparing these diseases to better understand how immune deviation may lead to pathological events and to find new therapeutic and.or preventive agents.     

Genetic variation in Th1/Th2 pathway genes and risk of non-Hodgkin lymphoma: a pooled analysis of three population-based case-control studies

The balance between T-helper 1 (Th1) and T-helper 2 (Th2) activity is critical in lymphoid cell development and differentiation. Immune dysfunction underlies lymphomagenesis, so an alteration in the regulation of key Th1/Th2 cytokines may lead to the development of non-Hodgkin lymphoma (NHL). To study the impact of polymorphisms in Th1/Th2 cytokines on NHL risk, we analyzed 145 tag single nucleotide polymorphisms (SNPs) in 17 Th1/Th2 cytokine and related genes in three population-based case-control studies (1946 cases and 1808 controls). Logistic regression was used to compute odds ratios (OR) for NHL and four major NHL subtypes in relation to tag SNP genotypes and haplotypes. A gene-based analysis adjusting for the number of tag SNPs genotyped in each gene showed significant associations with risk of NHL combined and one or more NHL subtypes for Th1 (IL12A and IL12RB1) and Th2 (IL4, IL10RB, and IL18) genes. The strongest association was for rs485497 in IL12A, which plays a central role in bridging the cellular and humoral pathways of innate resistance and antigen-specific adaptive immune responses (allele risk OR= 1·17; P(trend)= 0·00099). This SNP was also associated specifically with risk of follicular lymphoma (allele risk OR= 1·26; P(trend)= 0·0012). These findings suggest that genetic variation in Th1/Th2 cytokine genes may contribute to lymphomagenesis.     

Activation-induced deaminase heterozygous MRL/lpr mice are delayed in the production of high-affinity pathogenic antibodies and in the development of lupus nephritis

We previously reported that activation-induced deaminase (AID) heterozygous MRL/lpr mice have substantially lower levels of serum anti-dsDNA autoantibodies than AID wild-type littermates. Given the known functions of AID, here we examined whether this decrease in pathogenic autoantibodies in the heterozygotes was the result of a defect in class switch recombination, somatic hypermutation, or both. We report significant impairment of switch recombination to most isotypes except immunoglobulin G3 (IgG3) in vitro. However, serum levels of IgG were similar to AID wild-type levels even in very young mice. Mutation accumulation in the B cells from Peyer's patches also revealed reduced somatic hypermutation in the heterozygotes. Unlike the switch defect, the hypermutation defect probably resulted in an in vivo effect because the serum IgG antibodies from the heterozygotes were of strikingly lower affinity to dsDNA than serum IgG antibodies from wild-type littermates. This suggests that the somatic hypermutation defect resulted in impaired affinity maturation of autoantibodies in these mice and explains the low levels of specific anti-dsDNA antibodies in the heterozygotes. This correlated with a delay in the development of kidney damage. These results imply that AID levels impact the class switch recombination and somatic hypermutation mechanisms and directly implicate affinity maturation of autoantibodies in autoimmunity.     

Applicability of the IAIHG scoring system to the diagnosis of antimitochondrial/anti-M2 seropositive variant form of autoimmune hepatitis

BACKGROUND AND AIMS: According to the International Autoimmune Hepatitis Group (IAIHG) criteria, circulating antimitochondrial antibodies (AMA) do not support the diagnosis of autoimmune hepatitis (AIH). The aims of this study were to characterize a subset of patients with AIH who have AMA and antiM2 seropositivity, and to assess the applicability of the revised scoring system of the IAIHG in the diagnosis of this variant form of AIH. METHODS: Eighteen patients with AMA-AIH were enrolled and compared with 206 classical AIH and 85 primary biliary cirrhosis (PBC) controls. Human leukocyte antigen (HLA) class II alleles were determined by polymerase chain reaction (PCR) amplification with sequence-specific primers, and biopsies were blindly reevaluated. RESULTS: The patients with AMA-AIH were, on average, older than patients with classical AIH and had an hepatocellular pattern of elevated liver enzymes, hypergammaglobulinemia and lower levels of cholesterol, when compared with PBC controls. There were no histological signs of PBC or overlapping forms in any AMA-AIH biopsies. The majority of patients with AMA-AIH carried HLA antigens associated with classical AIH (DRB1*03, n = 5; DRB1*04, n = 7, and DRB1*13, n = 6). Pretreatment scores classified all AMA-AIH patients with probable (n = 17) or improbable (n = 1) AIH. After treatment, only 28% of AMA-AIH patients reached scores for definite diagnosis, compared with 90.1% of AIH-1 and 96.4 AIH-2. In the AMA-AIH group, only patients who relapsed after immunosuppressive drug withdrawal could be classified with definite AIH. CONCLUSIONS: AMA-AIH shares common features with classical AIH. The diagnosis of AMA-AIH may be swayed by the IAIHG criteria, rendering questionable the applicability of the revised scoring system to this variant form of AIH.     

What does the immunogenetic basis of rheumatoid arthritis teach us about the immunobiology of the disease?

Rheumatoid arthritis is a chronic inflammatory autoimmune disease in which, although the exact etiology is unknown, the contribution from genetic factors is approximately 60%. major histocompatibility complex alleles make the largest contribution to this genetic effect. The remainder is probably made up of an, as yet undefined, number of genes (～50–200) with low disease penetrance. Recent advances in genetic technology are now enabling us to start to identify some of these more moderate risk-conferring candidate genes. Evidence from functional studies of such genes is beginning to provide insight into the exact nature of the pathways and processes involved in disease susceptibility and expression. In this review, we will discuss how a growing number of genetic polymorphisms might underpin the immunological and molecular anomalies characteristic of rheumatoid arthritis. Specifically, we will focus on one particular pathway, T-cell activation, with an emphasis on the genetic polymorphism that influences antigen presentation and recognition in antigen-presenting cells, as well as those genes that influence the thresholds of antigen-receptor signaling in T lymphocytes.     

NONE TOO S.M.A.LL: the global challenge of severe malarial anaemia and its transfusion support

In endemic areas, the burden of malaria and anaemia converge together upon children, with severe malarial anaemia (SMA) accounting disproportionately for demands on limited blood supplies. The attributable morbidity and mortality from SMA remain high, and improved outcomes hinge in part on the timeliness, sufficiency and safety of transfusion support. The pathogenesis of SMA is complex, and depreciation kinetics (towards syndrome‐defining haemoglobin levels of <50 g/l) occur acutely or insidiously, and in relation to the parasite burden and host response. Beyond haemolysis of parasitized erythrocytes, mechanisms of bystander loss and reduced erythropoiesis figure prominently, with parallels to hyperhaemolysis syndrome. Involuntarily undertransfused children with SMA in low‐income countries (LIC) differ from those adults in high‐income countries (HIC) who deliberately renounce transfusion. Despite youth‐related advantages in the power to adapt to anaemia, critical reductions in oxygen‐carrying capacity illustrate the hierarchical impacts of organ anoxia, be it in terminal cardiorespiratory events or irreversible neurocognitive impairments in survivors. When resources permit, the dynamics of restored oxygen delivery by transfusion are particularly observable in SMA, as the triggers to transfuse are so much lower (and the odds of corresponding lactic acidosis are so much higher) than in HICs. Questions on the best haemotherapy approaches to SMA remain, be these in dosage, infusion rate, component preparation or matching options; these fundamental concerns now transcend those related to storage duration. As a persisting global scourge, SMA therefore keeps driving and facing the mandate to bank life‐preserving blood for those with the most to gain (and otherwise lose).     

Genetic diversity of the HLA system in human populations from the Sierra (Andean), Oriente (Amazonian) and Costa (Coastal) regions of Ecuador

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in a total of 1101 Ecuadorian individuals from three regions of the country, the Coastal region, the Andean region, and the Amazonian region, to obtain information regarding allelic and haplotypic frequencies and their linkage disequilibrium. We find that the most frequent HLA haplotypes with significant linkage disequilibrium in those populations are HLA-A*24～B*35～DRB1*04～DQB1*03:02, A*02～B*35～DRB1*04～DQB1*03:02, A*24～B*35～DRB1*14～DQB1*03:01, A*02～B*35～DRB1*14～DQB1*03:01 and A*02～B*40:02～DRB1*04～DQB1*03:02. The only non-Native American haplotype with frequency >1% shared by all groups was A*29～B*44～DRB1*07～DQB1*02. Admixture estimates obtained by a maximum likelihood method using HLA-B as genetic estimator revealed that the main genetic components for this sample of mixed-ancestry Ecuadorians are Native American (ranging from 52.86% to 63.83%) and European (from 28.95% to 46.54%), while an African genetic component was only apparent in the Coastal region (18.19%). Our findings provide a starting point for the study of population immunogenetics of Ecuadorian populations.