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PubMed1990

Serological interpretation--theoretical limits to information from blocking.

Contemporary immunogenetics uses a symbolism that tacitly assumes a one-to-one correspondence between genes, antigens, and antibody reagents that identify these. Thus a particular gene will be symbolized by an identifier, say X, and the reagent that supposedly uniquely identifies X is called anti-X. Ultimately, the precise relation between genes and antibody reagents will be determined by molecular techniques. Previous mathematical work has shown that by allowing a general relation (not constrained by symbolic conventions), alternative genetic descriptions can be found for some systems. This work predicts that when the relation is identified for these systems by molecular means, there will be an unresolved cross-reactivity, that is, there will not be a simple one-to-one correspondence between genes and the reagents used to identify them. This will contradict the notation in which the immunogenetic systems are described. Serology will have to be reinterpreted in terms of a more general notation that will allow for cross-reactivity. The focus of a mathematical model will switch from making inferences about genes, antigens, and antibodies in some system to analyzing genetics and serology as described by the notation. This paper investigates the information theoretically available from the serological operations of blocking, absorption, and elution. We show that, except for antigens (called undetectable) that mimic combinations of other antigens (in all cells in the system), blocking can theoretically reveal the relationship between antigens and antibodies in a system.

Antibodies↗
PubMed1980

Pre-eclampsia and changed paternity.

A review of 34, 201 multigravid deliveries found 47 patients who had severe pre-eclampsia after previous normotensive, non-albuminuric pregnancies. In 13 of these patients the affected pregnancy was apparently by a new father compared with 3 matched controls (P less than 0.01). This evidence supports the idea of a paternal immunogenetic factor in pre-eclampsia; immunogenetics.

Adolescent↗
PubMed2004

Long-term results of allogeneic penetrating limbo-keratoplasty in total limbal stem cell deficiency.

OBJECTIVE: To determine the prognosis of allogeneic penetrating limbo-keratoplasty in patients with total limbal stem cell deficiency and to find out if donor limbal stem cells survive in the long run. DESIGN: Noncomparative prospective case series. PARTICIPANTS: Forty-eight patients with total limbal stem cell deficiency. INTERVENTION: Allogeneic penetrating limbo-keratoplasty. All patients received systemic cyclosporin A and/or mycophenolate mofetil in the postoperative course. Thirteen patients received grafts with 0 to 1 HLA mismatches in the HLA-A, HLA-B, and HLA-DR loci; 13 patients received grafts with 2 to 6 mismatches; and 22 patients received untyped grafts. MAIN OUTCOME MEASURES: Long-term clear graft survival and survival of donor limbal stem cells. RESULTS: Five years postoperatively, 65% of the grafts with 0 to 1 mismatches, 41% of the grafts with 2 to 6 mismatches, and 14% of the untyped grafts were clear centrally (estimation according to Kaplan-Meier log rank test, P = 0.03). Immunogenetic analysis of epithelial cells from the surface of the graft could be performed successfully in 7 of 9 patients and revealed donor DNA in the epithelium of 5 of these 7 patients up to 56 months postoperatively. CONCLUSIONS: Long-term survival of donor epithelium could be demonstrated immunogenetically in patients undergoing allogeneic penetrating limbo-keratoplasty. Human leukocyte antigen-matched grafts seem to deliver better results than untyped grafts. Progress with matching and immunosuppressive strategies may further improve current results.

Adult↗
PubMed2002

Coeliac disease: changing views on gluten-sensitive enteropathy.

BACKGROUND: The continuing flow of scientific development in coeliac disease in the past decade points to the need for the formulation of a new concept of pathophysiology and clinical approach to the coeliac condition. Immunogenetic studies have shown a correlation of the disease to the HLA region on the short arm of chromosome 6; immunological research has led to the concept of a T-cell-driven immunologic response of the small intestine, with the identification of highly sensitive and specific antibodies; and our understanding of the histopathology of coeliac disease has changed dramatically, initiated by the proposition of a spectrum of gluten-sensitive enteropathy by Marsh in 1992. Clinical studies report a significant change in patient characteristics and epidemiology. The incidence of the disease has shifted to a majority of adult coeliacs, and it may present with less severe symptoms of malabsorption. Screening studies suggest an overall prevalence of up to 1 in 200-300. METHODS: Update on histopathology concentrating on the work of our research group. RESULTS: We specifically describe the work of our group in Arnhem concerning the identification and validation of the spectrum of intestinal histopathology in gluten-sensitive enteropathy, i.e. lymphocytic enteritis (Marsh I lesion), lymphocytic enteritis with crypt hyperplasia (Marsh II lesion), and villous atrophy, subdivided into partial villous atrophy (Marsh IIIA), subtotal villous atrophy (Marsh IIIB) and total villous atrophy (Marsh IIIC). Special attention is given to a subgroup of 'refractory coeliacs', including the identification of (pre-)malignant aberrant T cells in the intestinal mucosa of these patients. CONCLUSION: New data on immunogenetics, epidemiology, histopathology and patient characteristics point to a significant change of view on coeliac disease.

Celiac Disease↗
PubMed1997

An inflammatory, familial, inclusion body myositis with autoimmune features and a phenotype identical to sporadic inclusion body myositis. Studies in three families.

We describe the occurrence of an inflammatory inclusion body myositis in siblings of a single generation in three separate families. The disease in this total of seven patients was characterized by selective and early involvement of forearm and finger flexors, confirmed by MRI, and weakness of the quadriceps, triceps and foot extensors. Muscle biopsies in at least two members from each family showed endomysial inflammation, red-rimmed vacuoles, intracellular amyloid deposition and 15-18-nm tubulo-filaments within the vacuolated muscle fibres. Immunocytochemistry on serial muscle biopsy sections demonstrated an abundance of CD8+ cells invading non-necrotic, MHC-1-expressing muscle fibres. Immunogenetic studies showed the presence of the DR3 allele (DRB1*0301/0302) in all seven patients. The combination of the clinical, histological, immunopathological and immunogenetic features indicate that these patients have a disease identical to sporadic inclusion body myositis (s-IBM). We conclude that the classic, inflammatory, s-IBM can also occur in families (familial inclusion body myositis), in a pattern analogous to the familial occurrence of other autoimmune neurological diseases such as myasthenia gravis and multiple sclerosis. These observations strengthen the view that s-IBM behaves like other autoimmune diseases and has disease susceptibility linked to the DR3 allele.

Aged↗
PubMed2005

A candidate gene approach of immune mediators effecting the susceptibility to and severity of upper gastrointestinal tract diseases in relation to Helicobacter pylori and Epstein-Barr virus infections.

This review focuses on immunogenetic aspects of diseases of the upper gastrointestinal tract in which infectious agents may play a role in the aetiopathogenesis, such as Helicobacter pylori, Epstein-Barr virus (EBV) and HIV. Gastric adenocarcinoma is a common cancer all around the world, with declining incidences in Europe and high incidences in Asia and central and south America. Together with gastric atrophy and peptic ulcer disease, gastric adenocarcinoma belongs to the commonest upper gastrointestinal tract diseases. These diseases are multifactorial and factors such as smoking and dietary habits contribute to the pathogenesis. More recently, scientists have turned their eyes on the host. Functional polymorphisms in the genes regulating the host immune system may contribute to the susceptibility to and progression of disease. In multifactorial and polygenetic diseases, candidate gene studies of single nucleotide polymorphisms (SNPs) detect small to moderate relative risks. Unfortunately, only a few functional SNPs have been identified. The candidate gene approach can be seen as a useful first step in exploring causal pathways between genetic determinants and complex diseases such as those mentioned above. To date, little is known about the immunogenetics of upper gastrointestinal tract diseases. We review the literature on H. pylori, EBV and gene polymorphisms that affect key immune mediators influencing the pathogenesis of the inflammatory response, such as the genes that code for the IL-1 family, TNF-alpha, lymphotoxin alpha, and IL-10. IL-1, IL-10, lymphotoxin alpha and TNF-alpha polymorphisms increase the risk of upper gastrointestinal pathogenesis in H. pylori-infected patients, whereas IL-1 and TNF-alpha polymorphisms confer risk in EBV-infected patients.

Cytokines↗
PubMed2026

Wildlife Trade and Genetic Basis of Disease Susceptibility: A Review.

The surge in the trade of wildlife and wildlife products drives several species to extinction while coinciding with the increase in several zoonotic diseases. It is therefore essential to explore the roles of wildlife trade in disease transmission, and how the knowledge of genetics and immunogenetics can help in alleviating the attending challenges. Pathogen-driven selection plays a fundamental role in maintaining immune gene diversity, as individuals with alleles conferring resistance to endemic diseases have higher survival rate. However, anthropogenic disturbances, such as wildlife exploitation, can disrupt these evolutionary processes, leading to reduced genetic diversity and increased disease vulnerability. Advanced genomic tools, such as next-generation sequencing (NGS), whole-genome sequencing (WGS), CRISPR-Cas9 gene editing, genome-wide association studies (GWAS), epigenetics and transcriptomic analysis, can help identify immune gene variations and predict disease susceptibility in both wild and captive populations. Massive research targeting wildlife markets and the interface between the wild and the market players is necessary. It would be interesting to understand dynamics of pathogens and disease susceptibility, through the application of genetics and immunogenetics, thereby enhancing efforts to address the challenges posed by wildlife trade and zoonotic disease emergence.

Animals↗
PubMed1997

Primary association of HLA-B51 with Behçet's disease in Ireland.

AIMS/BACKGROUND: While a primary association of HLA-B51 with Behçet's disease (BD) in Japanese and Mediterranean patients supports an immunogenetic predisposition, this link is unclear in north western Europe. This study assessed HLA associations with BD, and HLA-B51 with certain clinical characteristics, in the Republic of Ireland, which has an ethnically homogeneous population. METHODS: HLA-A, HLA-B, and HLA-DR typing was performed in 24 BD patients, conforming to International Study Group criteria, and in blood donors, as controls. Patient records were retrospectively reviewed and patients reassessed clinically. RESULTS: A highly significant HLA-B51 association (corrected exact p value = 0.002, relative risk = 6.3) with BD was determined, despite a low B51 prevalence (25%) in patients. No other HLA type was associated. There was a significant B51 link with male sex in BD patients but no association with age at first manifestation/diagnosis, eye involvement, cyclosporin A therapy, or poor visual acuity was determined. CONCLUSIONS: This study supports a HLA-B51 immunogenetic predisposition, similar to Japanese patients, in Irish BD in an ethnically homogeneous population in north western Europe. However, owing to a low prevalence of B51 positivity in BD patients in Ireland, a multifactorial pathogenesis is suggested.

Adult↗
PubMed2006

Immunogenomics: molecular hide and seek.

Similar to other classical science disciplines, immunology has been embracing novel technologies and approaches giving rise to specialised sub-disciplines such as immunogenetics and, more recently, immunogenomics, which, in many ways, is the genome-wide application of immunogenetic approaches. Here, recent progress in the understanding of the immune sub-genome will be reviewed, and the ways in which immunogenomic datasets consisting of genetic and epigenetic variation, linkage disequilibrium and recombination can be harnessed for disease association and evolutionary studies will be discussed. The discussion will focus on data available for the major histocompatibility complex and the leukocyte receptor complex, the two most polymorphic regions of the human immune sub-genome.

Base Sequence↗
PubMed1986

Highly immunogenic artificial complexes based on synthetic immunopotentiating polyions (artificial antigens and vaccines).

An interpretive review of the theoretical and experimental data on the immunogenetic concept that "there are no strong and weak antigens, there are high and low responder genotypes," developed and upheld by the authors is presented. To achieve phenotypic correction (finding ways of turning genetically low responder individuals into high responder ones) the authors have developed complex antigens--artificial macromolecular complexes containing both the required antigenic determinants and adjuvant structures. Synthetic nonnatural carbohydrates and heterochain polyions with controlled structure (PAA, PVP, polyconidine quarternary salts) were shown to act as immunopotentiators, substituting the helper signal of T-cells. The authors' data confirm this immunogenetic principle for developing highly immunogenic preparations, prototypes of future vaccines.

Adjuvants, Immunologic↗
PubMed1998

Systemic lupus erythematosus in three ethnic groups: II. Features predictive of disease activity early in its course. LUMINA Study Group. Lupus in minority populations, nature versus nurture.

OBJECTIVE: To determine the factors associated with disease activity in patients with recent-onset (< or =5 years) systemic lupus erythematosus (SLE) who were of Hispanic, African-American, or Caucasian ethnicity. METHODS: Incident and prevalent cases of SLE, as defined by the American College of Rheumatology criteria for SLE, among the 3 ethnic groups were identified in Alabama (The University of Alabama at Birmingham) and Texas (The University of Texas-Houston Health Science Center and The University of Texas Medical Branch at Galveston). Variables from the sociodemographic, clinical, immunologic, immunogenetic, behavioral, and psychological domains were obtained using validated instruments. Disease activity was ascertained with the Systemic Lupus Activity Measure (SLAM). Stepwise domain regressions with SLAM score as the dependent variable were performed. Final ethnic-specific and overall regression models were obtained by entering variables that were retained in the domain regressions. RESULTS: SLAM scores at study entry were higher in the African Americans (mean +/- SD 12.6 +/- 6.9) and Hispanics (11.0 +/- 6.2) than in the Caucasians (8.5 +/- 3.7) (P < or = 0.001). The final overall regression model (R2 = 28%) for higher SLAM score included the following variables: African-American ethnicity, lack of private health insurance, abrupt disease onset, presence of anti-Ro antibodies, absence of HLA-DRB1*0301, higher levels of helplessness, and abnormal illness-related behaviors. CONCLUSION: Socioeconomic, immunologic, immunogenetic, behavioral, and psychological variables were all predictive of disease activity early in the course of SLE, irrespective of ethnic group. However, there remain ethnic group differences in disease activity that were not explained by these factors.

Adolescent↗
PubMed1999

Long-term outcome in mixed connective tissue disease: longitudinal clinical and serologic findings.

OBJECTIVE: To determine the long-term clinical and immunologic outcomes in a well-characterized cohort of 47 patients with mixed connective tissue disease (MCTD), including reactivity with U small nuclear RNP (snRNP) polypeptides. METHODS: Patients were followed up over a period of 3-29 years with immunogenetic and systematic clinical and serologic analysis. Sera were analyzed for reactivity with snRNP polypeptides U1-70 kd, A, C, B/B', and D, for anti-U1 RNA, and for anticardiolipin antibodies (aCL). RESULTS: The typical core clinical features of MCTD tended to develop over time; features of inflammation as well as Raynaud's phenomenon and esophageal hypomotility diminished, while pulmonary hypertension, pulmonary dysfunction, and central nervous system disease persisted, following treatment. A favorable outcome was observed in 62% of patients; 38% had continued active disease or had died, with death associated with pulmonary hypertension and aCL. All patients had autoantibodies to the U1-70 kd polypeptide of snRNP, and most were positive for anti-U1 RNA. An orderly progression of intramolecular spreading of autoantibody reactivity against snRNP polypeptides was observed, as was the novel finding of "epitope contraction" followed by disappearance of anti-snRNP autoantibodies during prolonged remission. CONCLUSION: These patients demonstrated the typical immunogenetic, clinical, and serologic findings of MCTD, and the condition rarely evolved into systemic lupus erythematosus or systemic sclerosis. The majority of patients had favorable outcomes, with pulmonary hypertension being the most frequent disease-associated cause of death. Intramolecular spreading of autoantibody reactivity against snRNP polypeptides was observed, followed by "epitope contraction" and ultimate disappearance of anti-snRNP autoantibodies during prolonged disease remission.

Autoantibodies↗
PubMed1994

HLA-DRB1 alleles in polymyalgia rheumatica, giant cell arteritis, and rheumatoid arthritis.

OBJECTIVE: Immunogenetic analysis has demonstrated that giant cell arteritis (GCA) and rheumatoid arthritis (RA) are associated with 2 different domains of the HLA-DR4 molecule. The present study was undertaken to evaluate whether polymyalgia rheumatica (PMR) immunogenetically resembles GCA or RA and to determine whether expression of HLA-DRB1 alleles can be used to detect heterogeneity among PMR patients. METHODS: Forty-six patients with PMR, 52 with GCA, 122 with seropositive RA, and 72 normal individuals were genotyped for HLA-DRB1 alleles by allele-specific amplification and subsequent oligonucleotide hybridization. RESULTS: The HLA-DRB1*04 allele was the most frequent among PMR patients (67%). While the expression of allelic variants of the HLA-DR4 family was restricted to HLA-DRB1*0401 and *0404/8 in RA patients, all HLA-DRB1*04 alleles, including B1*0402 and B1*0403, were represented in the PMR group. The distribution of HLA-DRB1 alleles among HLA-DRB1*04 negative patients was similar in those with PMR and those with GCA, and could be distinguished from that in RA patients. In particular, HLA-DRB1*01 alleles, which were found in most HLA-DRB1*04 negative RA patients, were underrepresented in patients with PMR and GCA. CONCLUSION: The distribution of HLA-DRB1 alleles in PMR resembles that found in GCA. PMR and GCA share the associated sequence polymorphism encoded by the second hypervariable region (HVR) of the HLA-DRB1 gene. The HLA-DRB1 association of PMR and GCA can be distinguished from that of RA, which is linked to a sequence motif in the third HVR of DRB1 alleles. The differential role of distinct domains on HLA-DR molecules suggests that multiple biologic functions are regulated by these molecules and that they contribute differently to disease mechanisms. The similarities in the distribution of HLA-DRB1 alleles in PMR and GCA indicates that HLA-DRB1 alleles are not predictive for progression of PMR to the vasculitic lesions that are pathognomonic for GCA.

Aged↗
PubMed1995

Analysis of anti-U1 RNA antibodies in patients with connective tissue disease. Association with HLA and clinical manifestations of disease.

OBJECTIVE: To determine the prevalence of anti-U1 RNA antibodies in connective tissue disease (CTD) patients and evaluate immunogenetic and clinical features of patients possessing these antibodies. METHODS: RNA immunoprecipitation was used to analyze patient and healthy control sera for the presence of anti-R1 RNA antibodies. Enzyme-linked immunosorbent assay and immunoblotting were used to determine small nuclear RNP (snRNP) polypeptide antibodies. HLA polymorphisms were determined by microcytotoxicity and DNA typing. RESULTS: Anti-U1 RNA IgM and IgG antibodies were found in 60% of anti-RNP positive patients. All of the anti-U1 RNA positive patients had anti-70K, and most had anti-A, (U1)snRNP polypeptide antibodies. HLA-DR2/DR4, as well as Raynaud's phenomenon and synovitis, were significantly increased in the anti-U1 RNA positive group. CONCLUSION: The presence of anti-U1 RNA antibodies correlates with anti-70K and anti-A polypeptide antibodies. In addition, the anti-U1 RNA positive CTD patient group is immunogenetically and clinically distinctive from the anti-U1 RNA negative patient group.

Adolescent↗
PubMed2004

Sjögren's syndrome associated with systemic lupus erythematosus: clinical and laboratory profiles and comparison with primary Sjögren's syndrome.

OBJECTIVE: To address the clinical, serologic, pathologic, and immunogenetic features of sicca syndrome that occurs in systemic lupus erythematosus (SLE), as well as its similarities to, and differences from, sicca syndrome that occurs in primary Sjögren's syndrome (SS). METHODS: A cohort of 283 consecutive unselected SLE patients was evaluated for the presence of associated SS using the American-European classification criteria. Clinical and laboratory parameters in SLE patients with SS (SLE-SS) were compared with those in SLE patients without SS (SLE-no SS) and with a group of 86 unselected patients with primary SS. RESULTS: SS was identified in 26 SLE patients (9.2%); the SS preceded the development of lupus in 18 of them (69.2%). Compared with the SLE-no SS group, patients with SLE-SS were significantly older, had a higher frequency of Raynaud's phenomenon, anti-Ro/SSA, anti-La/SSB, and rheumatoid factor, but had a significantly lower frequency of renal involvement, lymphadenopathy, and thrombocytopenia. Compared with the primary SS group, SLE-SS patients displayed a clinically similar sicca syndrome, but were significantly younger and had an increased frequency of perivascular infiltrates in the salivary glands associated with anticardiolipin antibodies in the serum. SLE-SS patients had a high frequency of the DRB1*0301 allele. This HLA profile distinguished the SLE-SS group from the SLE-no SS group, who had an increased frequency of DRB1*1501 and DQB1*0602 alleles, but was similar to the HLA profile of the primary SS group, who had an increased frequency of DRB1*0301. CONCLUSION: SLE-SS appears to constitute a subgroup of patients with distinct clinical, serologic, pathologic, and immunogenetic features, in whom SS is expressed as an overlapping entity and is largely similar to primary SS.

Adult↗
PubMed2006

Myositis-specific and myositis-associated antibodies in a series of eighty-eight Mediterranean patients with idiopathic inflammatory myopathy.

OBJECTIVE: To determine the prevalence of myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs) and their clinical and immunogenetic correlations in Mediterranean patients with idiopathic inflammatory myopathies. METHODS: Sera from 88 patients were studied for MSAs and MAAs by RNA and protein immunoprecipitation. HLA typing was performed by sequence-specific primer- and sequence-specific oligonucleotide-polymerase chain reaction and serology. Statistical analyses were performed with Student's t-test and Fisher's exact test. Cumulative survival probabilities were estimated by the Kaplan-Meier method and Cox regression analysis. RESULTS: Twenty-eight patients (30%) had MSAs, most commonly antisynthetase antibodies (23.9%). Six patients (7.5%) had anti-Mi-2 antibodies. No anti-signal recognition particles were found. Arthritis, mechanic's hands, interstitial lung disease, and sicca syndrome were more prevalent in patients with antisynthetase antibodies. Dysphagia and the need for more treatment courses were more frequent in patients who were anti-Mi-2 positive. Forty-three patients (48%) had MAAs, 20 (22%) with anti-Ro 60 and 18 (20.4%) with anti-Ro 52. Ten patients (11.4%) were positive for anti-PM-Scl, 6 (6.8%) for anti-RNP, and 1 for anti-Ku antibodies. Patients with PM-Scl, RNP, or Ro antibodies were more often classified as having overlap syndrome. Immunogenetic studies found a significant association between HLA-DR3 and the presence of antisynthetase antibodies (P = 0.049), anti-PM-Scl antibodies (P = 0.017), and interstitial lung disease (P = 0.03). No statistically significant differences in mortality, survival, or clinical course were observed between patients positive for MSAs or MAAs and the remaining patients. CONCLUSION: These results are consistent with those from other published series, although some differences warrant consideration. Autoantibody studies may be useful for defining more homogeneous groups of patients with idiopathic inflammatory myopathies.

Adult↗
PubMedDate not supplied

The pathology of head and neck tumors: the lymphoepithelial lesion and Sjögren's syndrome, Part 16.

The clinical disorder Sjögren's syndrome and its putative histologic marker in salivary tissues, the lymphoepithelial lesion, have been and continue to be sources of confusion as well as the subjects of extensive immunologic and pathologic research. At the present time, Sjögren's syndrome is defined as a lymphocyte-mediated exocrinopathy but definition does little justice to the profound immunogenetic basis of the syndrome. This report presents a contemporary review of the lymphoepithelial lesion and the syndrome and presents a hypothesis of pathogenesis based on a graft vs host disease-like disorder. The hypothesis incorporates the immunogenetic, immunoregulatory, and neoplastic aspects of Sjögren's syndrome.

Carcinoma↗
PubMed1991

Aspartic acid at position 57 of the HLA-DQ beta chain is protective against future development of insulin-dependent (type 1) diabetes mellitus.

Insulin-dependent (Type I) diabetes mellitus is a chronic autoimmune disease. From studies in discordant twins and multiplex families a long prediabetic period has been reported. In a population-based program started in 1983, fifteen individuals at possible risk for future Type I diabetes were followed for up to 74 months. Two individuals (13%) developed Type I diabetes. These probands were characterized by the presence of high-level cytoplasmic islet cell antibodies (ICA), complement-fixing ICA, and an impaired first-phase insulin response after intravenous glucose load. Both were homozygous for a high-risk immunogenetic marker of Type I diabetes, i.e., non-Asp at codon 57 of the HLA-DQ beta chain. In all other subjects studied, the immunogenetic marker that confers "dominant resistance", aspartic acid at codon 57, was found. On the basis of our data we conclude that a combination of assays which determine ICA, first-phase insulin release, and HLA-DQB1 polymorphisms will identify individuals with a high probability of developing Type I diabetes at the population level. Conversely, HLA haplotypes positive for aspartic acid seem to confer resistance to the disease.

Adult↗