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PubMed1993

Immunogenetic findings in glomerulonephritis.

In the 19th century, several authors recognized that some renal diseases tend to run in families. Alport pointed to the constellation of nephritic urinary sediment, hearing loss and progression into renal failure. Today this is recognized to result from abnormal basement membrane (BM) collagen synthesis. Recently it has been recognized, however, that other forms of glomerulonephritis may also run in families. In about 10% of patients with glomerulonephritis one or more sibling also suffers from glomerulonephritis. Genetically determined derangements of immune regulation may play a role in the genesis of primary chronic glomerulonephritis. Potentially associated immunogenetic abnormalities include inherited defects of the complement system, increased prevalence of certain HLA-types, altered frequencies of polymorphisms in immunoglobulins and TCR genes and others. This overview summarizes immunogenetic studies performed in patients with glomerulonephritis with special emphasis on patients with mesangial IgA GN.

Complement System Proteins↗

PubMed1996

The diffuse infiltrative lymphocytosis syndrome. Clinical and immunogenetic features in 35 patients.

OBJECTIVE: To study the epidemiological, clinical, serological and immunogenetic features of the diffuse infiltrative lymphocytosis syndrome (DILS). DESIGN: Consecutive series of 35 patients with DILS diagnosed from 1992 to 1995 in a cohort of 4100 outpatients infected with HIV-1. METHODS: Thirty-five individuals with DILS were ascertained from this cohort and followed for 720 patient-months. Clinical, serological and immunogenetic features of these patients were studied and their demographics were compared with the rest of the outpatient population. RESULTS: DILS was found to be more prevalent in African Americans (60%) than in Caucasians (26%) or Mexican Americans (14%) [odds ratio (OR), 2.32; 95% confidence interval (CI), 1-12-4.81; P = 0.02] and in persons with male-to-male transmission of HIV-1 (71%) (OR, 2.82; 95% CI, 1.29-6.29; P = 0.007). All patients had bilateral parotid gland enlargement. The majority had sicca symptoms. The most common extraglandular sites of disease were lung (31%), muscle (26%), and liver (23%). Four patients had biopsy-proven polymyositis. Thirteen patients met the 1993 Centers for Disease Control and Prevention case definition of AIDS. Sixteen (52%) patients expressed human leukocyte antigen (HLA)-DRS (DRB1*1102), DR6 (DRB1*1301, *1302), or DR7, and 11 (36%) expressed HLA-DR2. CONCLUSIONS: DILS is more common in African Americans and in persons with male-to-male transmission of HIV-1. HIV-associated polymyositis appears to occur in the setting of DILS.

Adult↗

PubMed1997

Is there an immunogenetic basis for Peyronie's disease?

PURPOSE: Despite numerous studies, there has been no definitive HLA association with Peyronie's disease. Results of available studies have been reviewed and compared to determine if the cumulative evidence supports any immunogenetic, HLA association with Peyronie's disease. MATERIALS AND METHODS: Data from reports of HLA associations with Peyronie's disease were reanalyzed by categories of reported HLA class I or class II antigens in comparison with recently available large population analysis of the frequencies of these antigens in the normal population. Data were also considered by whether they were derived from population or family analyses. RESULTS: The results of 4 series of patients testing an association of Peyronie's disease with the HLA class I antigens, in particular the B7 related antigens, were contradictory. A B7 association was not confirmed in 2 larger series and, in fact, the B7 related antigens were observed in frequencies expected in a normal population, suggesting that the associations observed in the smaller series were due to chance. An association with the HLA class II antigen, DQ2, was found in 1 of the larger series. Reported family studies suggest a genetic basis for Peyronie's disease but do not indicate a gene closely linked to the HLA complex. CONCLUSIONS: Considering all available data, Peyronie's disease appears to be multifactorial in pathogenesis. Because Peyronie's disease is likely heterogeneous and because available studies have analyzed serologically defined HLA antigens, future studies to define HLA alleles molecularly and to characterize patient subgroups may clarify an immunogenetic basis.

Autoimmune Diseases↗

PubMed1996

Acquired subepidermal bullous diseases associated with psoriasis: a clinical, immunopathological and immunogenetic study.

Clinical, immunopathological and immunogenetic studies of four patients with a subepidermal bullous disease associated with psoriasis were carried out to determine the true nature of the blistering disease and to investigate further the relationship between psoriasis and acquired subepidermal bullous diseases. Autoantibodies in all four patients bound to the epidermal side of salt-split skin by indirect immunofluorescence and detected the major bullous pemphigoid (BP) antigens by immunoblotting. One had additional IgA autoantibodies binding an epidermal polypeptide of 270/280 kDa and another had circulating IgG autoantibodies which detected both BP and epidermolysis bullosa acquisita (EBA) antigens. All patients had active psoriasis at the onset of the bullous disease. Three patients were being treated with tar when blisters developed; one patient also received UVB radiation and experienced a relapse after exposure to sunlight. HLA phenotypes in three patients were determined. All the patients responded well to methotrexate. These findings demonstrate that BP is the subepidermal bullous disease most associated with psoriasis. Changes at the basement membrane zone in psoriasis may be responsible for the heterogeneous antibody response and may trigger the bullous disease, as may antipsoriatic treatment including tar and UV radiation. However, common immunogenetic mechanisms may play a crucial part in this disease association.

Aged↗

PubMed1996

Immunogenetic factors that may contribute to ethnic differences in renal allograft survival.

In the United States, allocation of cadaveric kidneys is federally regulated and based on the concept of equal access to all patients, regardless of race, sex, age, or socioeconomic status. Nevertheless, it has been widely reported that African American patients with renal disease wait longer for kidney transplantation and, once transplanted, have poorer graft survival. We have assessed immunogenetic factors that may contribute to ethnic differences in allograft survival by examining the distributions of ABO blood groups, HLA antigens and haplotypes, percent reactive antibody (PRA), age, and gender in our local patient population. Approximately 62% of patients at our transplant center waiting for renal transplantation are African American; 39% are female. Age distribution is comparable to that reported nationally. ABO blood groups of patients on the waiting list are distributed similarly to those reported nationally for other renal patients. Sensitization to HLA antigens, through either blood transfusion, prior transplant, or pregnancy, has been strongly associated with poorer graft survival. Although, as expected, distribution of PRA was significantly different for males versus females at one time point, it did not differ between ethnic groups in our patient population. HLA polymorphism was assessed by comparisons of HLA allele and haplotype frequencies determined by analyses of African American and Caucasian families typed in our program since 1991. Haplotypes observed in each ethnic population were subjected to a variety of statistical analyses. Coefficient of contingency and Cramer's V statistic (measures of degree of association) were consistently higher for Caucasian haplotypes than for those of African Americans. Significantly more unique HLA haplotypes were observed among African American families than among Caucasian families. Thus, our data provide evidence for greater HLA linkage disequilibrium in Caucasians than in African Americans. HLA antigen and haplotype polymorphisms are likely, therefore, to be major immunogenetic factors contributing to ethnic differences in renal allograft survival.

Adolescent↗

PubMed1997

Relapsing polychondritis: clinical and immunogenetic analysis of 62 patients.

OBJECTIVE: In this study we describe clinical and immunogenetic findings in 62 unselected patients with relapsing polychondritis. METHODS: In a multicenter study, clinical data of 26 (41.9%) female and 36 (58.1%) male patients were collected. HLA-DR specificities were identified in 60, and the frequencies were compared with those in healthy controls. RESULTS: The median age at the time of diagnosis was 46.6 years (range 17 to 86). 58 (93.5%) patients had auricular chondritis, 31 (50.0%) ocular symptoms, 35 (56.5%) nasal involvement. Involvement of joints (53.2%), respiratory system (30.6%), skin (24.2%), cardiovascular system (22.6%), central nervous system (9.7%), and kidneys (6.5%) was found as well. 22 (35.5%) patients had associated diseases such as systemic lupus erythematosus or rheumatoid arthritis. Susceptibility to relapsing polychondritis was significantly associated with HLA-DR4 (p < 0.001). There was no difference in the frequency or distribution of DRB1*04 subtype alleles between patients and healthy controls. The extent of organ involvement was negatively associated with HLA-DR6 (p < 0.011). CONCLUSION: Immunogenetic findings as well as similarities and overlapping clinical symptoms with other autoimmune or rheumatic diseases suggest that immunological mechanisms play a major role in the pathogenesis of relapsing polychondritis.

Adolescent↗

PubMed1990

Immunogenetic analysis of bone marrow aspirates in patients with non-Hodgkin lymphomas.

The immunogenetic analysis (IGA) on the staging bone marrow aspirates in 15 patients with non-Hodgkin lymphoma (NHL) is reported. We found the sensitivity of IGA and morphologic examination in detecting bone marrow involvement by malignant lymphoma to be 91% and 82%, respectively. In 11 cases there was agreement between the morphologic findings and IGA. In 8 of these 11 cases, IGA confirmed the morphologic involvement of the bone marrow by demonstrating clonal rearrangement of either the immunoglobulin heavy- and/or light-chain or the T-cell receptor beta chain (TCR) genes. In 3 of these 11 cases, morphology showed no involvement and IGA showed germline configurations for both the immunoglobulin heavy- and light-chain or the TCR genes. In 2 additional cases the techniques proved to be complementary, as involvement was detected by only 1 of the 2 procedures. In 1 of these 2 cases, IGA showed gene rearrangement while morphologic examination was negative for involvement by NHL, while in the other case, morphologic examination showed involvement by NHL, but IGA did not show gene rearrangement. IGA was also useful in determining the clonality of solitary lymphoid nodules in the 2 remaining cases when morphologic interpretation was equivocal. In the 12 cases with bone marrow involvement, the immunophenotype and immunogenotype agreed in 11 cases. In the one case in which there was a discordance between the immunophenotype and immunogenotype, the immunophenotype was incorrectly interpreted as B-cell lineage, while the immunogenotype demonstrated a T-cell lineage. IGA also demonstrated a clonal population in 1 case of T-chronic lymphocytic leukemia where other techniques could not demonstrate the clonality of the pathologic process. IGA analysis may detect bone marrow involvement in NHL which may not be detected by morphologic examination because of patchy distribution.

B-Lymphocytes↗

PubMed1990

Immunogenetic associations of scleroderma-related antinuclear antibodies.

Patients selected for the presence of scleroderma-related antibodies (anti-DNA-topoisomerase I [anti-topo I; n = 43], anticentromere antibody [ACA; n = 63], or anti-Pm-Scl [n = 12]) were studied for class I and class II major histocompatibility complex antigens, as well as for Gm and Km allotypes. Anti-topo I was associated with HLA-DR5 (70% of patients versus 30.6% of controls; Pcorr = 0.0018, relative risk [RR] = 5.3). All patients with anti-Pm-Scl were positive for HLA-DR3 (versus 23.5% of controls; Pcorr less than 0.001); 6 of these patients were DR3/4 heterozygous (50% versus 3.5% of controls; Pcorr less than 0.001, RR = 27.3). Patients with ACA were frequently positive for HLA-DR1, DR4, or DRw8, with 73.7% demonstrating at least 1 of these alleles (versus 41.2% of controls; Pcorr = 0.0152, RR = 4.0). This group of ACA-positive patients who had DR1, DR4, and/or DRw8 consisted mainly of a subgroup of patients with rheumatoid arthritis. We conclude that different class II major histocompatibility complex antigens influence the formation of anti-topo I and anti-Pm-Scl. Important clinical differences between these patient groups and the immunogenetic heterogeneity support the notion of different antibody-defined scleroderma subsets.

Antibodies, Antinuclear↗

PubMed1993

Clinical, serologic, and immunogenetic studies in childhood-onset systemic lupus erythematosus.

OBJECTIVE: To determine the frequency of systemic lupus erythematosus (SLE)-associated clinical manifestations, autoantibodies, and HLA class II alleles in a large cohort of patients with childhood-onset SLE. METHODS: Eighty children with SLE onset before age 18 (27 before age 11) were studied for the frequency of renal, neuropsychiatric, and hematologic complications as well as for anti-native DNA, Ro, La, Sm, and U1 RNP autoantibodies. HLA-DR, DQ, and DP alleles were determined by oligotyping. The results were compared with findings in 213 adults with SLE onset at or after age 18 years. RESULTS: Renal involvement was more frequent in those with childhood-onset SLE, especially those with onset before age 11 (82%, compared with 53% in adults). Anti-U1 RNP was more common in American blacks with SLE onset before age 18. HLA-DRB1*0301, DQA1*0501, DQB1*0201 was more common in Caucasians and DRB1*1503, DRB5*0101, DQA1*0102, DQB1*0602 in American blacks, regardless of age at SLE onset. Anti-Sm autoantibodies were most highly associated with HLA-DQA1*0102 and DQB1*0602. CONCLUSION: While childhood-onset SLE shares many immunogenetic and serologic similarities to adult-onset disease, important clinical differences nevertheless exist in children with this disease.

Adolescent↗

PubMed1997

Immunogenetic similarities between patients with Felty's syndrome and those with clonal expansions of large granular lymphocytes in rheumatoid arthritis.

OBJECTIVE: Patients with chronic clonal proliferation of large granular lymphocytes (LGL leukemia) often have splenomegaly, neutropenia, and rheumatoid arthritis (RA), thereby resembling the manifestations observed in patients with Felty's syndrome. The present study sought to determine whether patients with these disorders represent 2 distinct subsets of neutropenic RA. METHODS: Prospective cohort study of outpatients attending clinics in university and private hospitals and in offices of private practice physicians. Twenty-two patients with Felty's syndrome and 22 patients with LGL leukemia, 10 of whom had RA, were studied. HLA genotyping was performed on peripheral blood mononuclear leukocyte genomic DNA. RESULTS: Nineteen of the 22 patients with Felty's syndrome (86%) were DR4 positive. Nine of the 10 patients with LGL leukemia plus RA were also DR4 positive. In contrast, only 4 of the 12 patients with LGL leukemia without RA (33%) were DR4 positive, a frequency that was within the normal range. CONCLUSION: The finding of an equally high prevalence of DR4 in patients with Felty's syndrome and in those with LGL leukemia plus RA suggests that both disorders have a similar immunogenetic basis and are parts of a single disease process rather than 2 separate disorders.

Arthritis, Rheumatoid↗

PubMed1998

D-penicillamine-induced pancreatic islet autoantibody production is independent of the immunogenetic background: a lesson from patients with Wilson's disease.

D-penicillamine (d-PA) was reported to induce various immunological abnormalities including production of autoantibodies to insulin. These abnormalities were mainly described in patients with primary immunological disorders such as rheumatoid arthritis. In order to clarify whether d-PA-induced immune disorders are restricted to patients genetically prone to develop autoimmune diseases or to a direct drug effect, we tested for the presence of various autoantibodies and for molecular HLA typing in 17 patients with Wilson's disease treated with this drug. In 2/17 patients, low-titer (10 JDFU) circulating islet cell autoantibodies (ICA) were detected, while another patient was positive for the presence of insulin autoantibodies. None of the sera tested showed reactivity for glutamic acid decarboxylase or ICA512. Five of twelve patients were positive for anti-single-stranded DNA autoantibody. Molecular HLA typing of the autoantibody-positive subjects showed that they carry HLA haplotypes not associated with insulin-dependent diabetes. The insulin response to intravenous glucose tolerance test in two patients with autoantibodies was found to be normal. A second blood testing of the autoantibody-positive patients 5 months following initial evaluation revealed conversion to negativity in all three. Our results suggest that d-PA-induced autoantibodies in patients with Wilson's disease are independent of the immunogenetic background characteristics of diabetes.

Adolescent↗

PubMed2006

Multiparameter analysis of immunogenetic mechanisms in clinical diagnosis and management of inflammatory bowel disease.

The integrity of the intestinal mucosa depends on a functional coordination of the epithelium, lumenal microorganisms, and the local immune system. The mammalian immune system is superbly organized for innate and adaptive recognition of microbial antigens, a defensive capacity that must be balanced against the tissue damage produced by immune activity to preserve normal intestinal function. Inflammatory bowel disease (IBD) is generally thought to reflect an impairment in this balance, due to a combination of host genetic traits that shift the balance of immune and epithelial function to commensal microbiota, and perhaps the composition or activity of certain microbial elements as well. There has been much progress defining the fundamental disorders of these host traits, immunologic processes, and microbial targets in inflammatory bowel disease. Other fields of clinical and geologic microbiology are teaching us about the dynamic interaction of commensal bacteria with their host environment. These lines of investigation have revealed not only important insights about inflammatory bowel disease (IBD) pathogenesis, but also defined technologies and tools useful for its diagnosis and clinical management. This review focuses on these advances at the translational interface. We will first consider the innate anti-microbial response, centering on the utility of NOD2 genotyping for predicting disease susceptibility, prognosis, and therapeutic response profile. We will then turn to the adaptive anti-microbial response, focusing on the application of antibodies to fungal and bacterial species and products for Crohn's disease (CD) diagnosis and prognosis, and immunogenetics of T cell immunosuppression management. Finally, we will describe autoimmune mechanisms in IBD, with particular attention to autoantibodies in IBD diagnosis and infliximab responsiveness. We will conclude with the concept of multiparameter analysis of patients, to refine patient characterization and stratification in diagnosis and clinical management.

Animals↗

PubMed1996

Immunogenetic profile of psoriasis vulgaris: association with haplotypes A2,B13,Cw6,DR7,DQA10201 and A1,B17,Cw6,DR7,DQA10201.

Psoriasis vulgaris is a skin disease with an immunological and genetic background present in 1-3% of the population. We studied the genetic susceptibility to psoriasis vulgaris in Finns with serological HLA typing and genomic HLA class II typing of the DQ and DP loci to evaluate the risk of developing psoriasis. The haplotypes most frequently distinguishing between psoriatics and controls were those that carried Cw6 (P < 10(-8)), DQA1*0201 (P = 9.3 x 10(-6)) and DR7 (P = 3.9 x 10(-5)). The two most frequent marker haplotypes were A2,B13,Cw6,DR7, DQA1*0201 and A1,B17,Cw6,DR7,DQA1*0201, which were not found among the control subjects. A deficit of haplotype B8,DR3,DQ2 (2 out of 124 in the patients versus 15 out of 106 in the controls, P = 1.5 x 10(-4)) was found, and this was in accordance with a slightly decreased frequency of DQA1*0501 (P = 3.1 x 10(-2)), which was usually linked with this haplotype. These results stimulate the research for a genetic resistance factor in psoriasis. Thus, this report sheds further light on the immunogenetic background of psoriasis in Finland. We conclude that the inheritance of psoriasis has a polygenic mode, in which the Cw6,DR7,DQA1*0201 combination seems to be important (P = 7.5 x 10(-7), relative risk 24.4, aetiological factor 0.29).

Adult↗

PubMedDate not supplied

Hypergammaglobulinemic purpura of Waldenström. (A report of serologic and immunogenetic studies and long-term follow-up in 18 patients).

Data from a study carried out on a group of 18 patients with hypergammaglobulinemic purpura of Waldenström (HPW) followed-up for 3-14 years are reported in this paper. In 11 patients the syndrome was considered to be idiopathic, while in the remaining 7 it was associated with Sjögren's syndrome (SS). A marked (17/1) female prevalence was observed. Purpura was the presenting clinical manifestation in 9 patients, but it occurred at different points during the course of the disease; Raynaud's phenomenon was present in one third of patients. Serum gammaglobulin levels were higher than 2.2 g/dl in all the cases and higher than 3 g/dl in 9 cases. Immune complexes were detected in all patients. A significant serologic finding in our case series was represented by the frequency of anti-Ro (16/16) and anti-La (14/15) antibodies, clearly higher than that reported in SS patients. HLA typing showed a marked increase of B8 and DR3 antigens as well as A1,B8,DR3 haplotype, never reported in other autoimmune diseases. On the basis of serologic and immunogenetic features, HPW seems a clearly distinguishable entity among autoimmune vasculitis.

Adult↗

PubMed1988

Epidermolysis bullosa letalis: an immunogenetic disease of extraembryonic ectoderm?

A newborn male infant with epidermolysis bullosa letalis died at age 6 weeks of septicemia. He had many congenital ectodermal abnormalities and a rudimentary thymus. The spleen had no germinal centers and the lymph nodes lacked follicles. Cytotrophoblast of the amniochorion was sparse and the amniotic epithelium was distorted. Immunohistologic studies of amniotic epithelium revealed the unprecedented presence of trophoblast antigens. Before birth of the patient, the parents had a 5-year history of infertility; after death of the patient, the mother sustained a ruptured tubal pregnancy that necessitated blood transfusions and surgical removal of the tube. She subsequently became pregnant a third time and was delivered of a normal child. The wife shared four major histocompatibility (HLA) antigens with her husband. The parents' immunogenetic characteristics and the immunopathologic features and extraembryonic membranes of the child are considered in terms of maternal responses to trophoblast antigens.

Amnion↗

PubMed1991

Management of complex immunogenetics information using an enhanced relational model.

Flow cytometry has become a technique of paramount importance in the armamentarium of the scientist in such domains as immunogenetics. In the PENGUIN project, we are currently developing the architecture for an expert database system to facilitate the design of flow-cytometry experiments. This paper describes the core of this architecture--a methodology for managing complex biomedical information in an extended relational framework. More specifically, we exploit a semantic data model to enhance relational databases with structuring and manipulation tools that take more domain information into account and provide the user with an appropriate level of abstraction. We present specific applications of the structural model to database schema management, data retrieval and browsing, and integrity maintenance.

Cell Separation↗

PubMed1996

Reverse immunogenetics: from HLA-disease associations to vaccine candidates.

Analysis of the human leukocyte antigens (HLA) in patients with either infectious or autoimmune diseases has led to the identification of several HLA alleles associated with either resistance or susceptibility to disease. Understanding the role of HLA molecules in the presentation of peptide antigens to T cells has led to the use of 'reverse immunogenetics': a novel approach to analysing the key antigenic peptides that are presented by the relevant HLA molecules. Recent advances in the analysis of naturally occurring peptides bound to HLA molecules has allowed the direct identification of antigenic peptides from living cells and has supported the development of vaccine candidates, such as the liver-stage antigen 1 in malaria.

Animals↗

PubMed2005

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.

Animals↗