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Biomedical subjects

C C McCombs

Publications and source records attributed to C C McCombs.

At least 19 recordsLinked to original sources
PubMed1996

An autosomal screen for genes that predispose to celiac disease in the western counties of Ireland.

Celiac disease is a strongly heritable gastrointestinal illness that is an especially important model of the genetically complex multifactorial immune mediated diseases. The HLA component of celiac disease (a specific HLA-DQ heterodimer)is largely established and is relatively uncomplicated, and the environmental component (gluten and related grain storage proteins in the diet) is remarkably well understood. Previous family studies of celiac disease suggested that there is at least one important non-HLA locus. This locus may be a stronger genetic factor than HLA, and it apparently has a recessive mode of inheritance. We used a three step genome screening protocol to identify loci that contribute to celiac disease in the western counties of ireland, a region with the highest prevalence of celiac disease in the world. The most significant of several possible non-HLA loci that we found was on chromosome 6p about 30 cM telomeric from HLA. It has a multipoint maximum lod score of 4.66 (compared with 4.44 for HLA-DQ) and appears to have a recessive mode of inheritance. Our study localizes and provides strong evidence for linkage of at least one non-HLA locus to celiac disease and may serve as a prototype for an efficient approach to screening the human genome for loci that contribute to complex diseases.

Adolescent↗
PubMed1996

HLA-DR, DQ genotypes of celiac disease patients and healthy subjects from the West of Ireland.

Celiac disease (CD) has one of the strongest class II HLA associations of any human illness. We used DNA-RFLP typing to study the class II HLA genotypes of celiac disease patients from the West of Ireland, the geographic area with the highest rate of celiac disease in the world. We confirmed the high frequency of HLA-DR3 in this population, and we were also able to demonstrate the additional risk of developing celiac disease imparted by HLA-DR7. This was done by clearly distinguishing DR7,DQ2 haplotypes from DR7,DQ9 haplotypes, and by "subtraction analysis" of haplotype frequencies. As reported in other populations, most of the patients without DR3 were heterozygous for DR7 and DR11 or 12 (DR5), or had DR4. We used PCR-RFLP and direct sequencing of amplified DNA to examine HLA-DR4 subtypes. The frequency of HLA-DR4 was markedly decreased in patients compared with controls (p = 0.000001) and there was a significant alteration of DR4 subtypes of the patients compared with controls (p = 0.0227). Moreover, all of the CD patients (5 of 5) with DR4 had a haplotype associated with the DQB1*0302 allele compared with only 11 of 23 control subjects with DR4. Our results in this population with exceptionally high risk of CD strongly support the DQ heterodimer hypothesis and suggest that the recently described sequence difference between the DQB1*02 alleles of DR3 and DR7 may contribute to a synergistic increased risk when these haplotypes are inherited together. In addition, our findings suggest a role for HLA-DQ in DR4-associated CD.

Celiac Disease↗
PubMed1995

T cell receptor gamma gene polymorphisms and class II human lymphocyte antigen genotypes in patients with celiac disease from the west of Ireland.

Although celiac disease has one of the strongest human lymphocyte antigen (HLA) class II associations of any human illness, it is clear that at least one gene that is not linked to the HLA region also is required for its pathogenesis. The occurrence of large numbers of gamma delta T cells in the bowel mucosa of patients and the recent description of T cell receptor (TCR) gamma chain polymorphic variants identified by restriction fragment length polymorphism analysis led the authors to examine TCR gamma genotypes in relation to HLA-DR, DQ genotypes in 89 patients with celiac disease and 55 control subjects from the West of Ireland. The overall frequency of TCR gamma genotypes in patients and control subjects was comparable. However, most of the patients had 1 of 3 HLA-DR3 genotypes (DR3/15, 3/7, or 3/3), and there was a significant alteration of the expected frequency of TCR gamma genotypes among patients with these three genotypes. The major differences were an increased association of HLA-DR3 homozygosity, with TCR gamma genotypes having a 16.0 kb fragment and an increased frequency of DR3/7 heterozygosity and decreased frequency of DR3/15 heterozygosity, respectively, in association with the TCR gamma 13.0/11.3 kb genotype. Based on their results, there is the possibility that an interaction between the products of two polymorphic and unlinked gene regions contributes to the pathogenesis of celiac disease.

Celiac Disease↗
PubMed1994

Celiac disease: clinical features and pathogenesis.

Celiac disease is a fascinating illness, from both a clinical and research perspective. Most clinicians consider a diagnosis of celiac disease when a young patient has classic signs and symptoms of steatorrhea and severe malabsorption. However, the typical gastrointestinal symptoms often are absent. The patient may only have subtle signs of chronic malnutrition or nonspecific gastrointestinal complaints. Celiac disease is not diagnosed commonly in the United States, at least in part because of a low clinical index of suspicion. A diagnosis of celiac disease is confirmed by a small bowel mucosa biopsy. A dramatic clinical response to a gluten-free diet verifies the diagnosis, and provides a cost-effective treatment free of significant side effects. Strict adherence to the prescribed diet usually results in a complete resolution of the symptoms and mucosal histopathologic changes. The serious, long-term complication of intestinal lymphoma also may be prevented. To the clinical investigator, celiac disease is an important model of the HLA-associated immune-mediated illnesses. A specific HLA-DQ heterodimer is found in 95% of patients, representing perhaps the strongest association of any illness with a specific class II HLA molecule. In addition, an important environmental trigger (gluten) has been identified, providing a unique opportunity to study the interaction of gene products and environmental factors in the pathogenesis of an immune-mediated disease.

Celiac Disease↗
PubMed1993

Evidence for an ongoing role of class I histocompatibility molecules for the production of interleukin-2 in response to suboptimal concentrations of phytohaemagglutinin.

To examine the role of cellular interactions involving class I histocompatibility antigens in the response to low concentrations of phytohaemagglutinin, we studied the effect of antibodies to components of these antigens on proliferative responses, interleukin-1 and interleukin-2 production, and IL-2 receptor expression. Antibody to human beta 2-microglobulin (beta 2m) had an inhibitory effect both on IL-2 accumulation at 48 h of culture and on the proliferative response 24 h later. Exogenous IL-2 completely reconstituted the inhibited proliferative responses, and also restored the modest decrease in IL-2 receptor expression that was induced by anti-beta 2m. Pretreatment of either purified monocytes or T cells with anti-beta 2m had a similar inhibitory effect both on proliferation and on interleukin-2 production. By contrast, IL-1 production by LPS- or silica-stimulated monocytes was not affected by this antibody. Kinetic experiments demonstrated that anti-beta 2m was equally inhibitory when added at the initiation of culture or after 24h, and significant inhibition occurred when the antibody was added as late as 48 h. Our results are consistent with an ongoing role for class I antigens in the cellular interactions between lymphocytes and accessory cells required for the production of IL-2.

Adult↗
PubMed1991

Evidence for a dominant gene mechanism underlying coeliac disease in the west of Ireland.

Although coeliac disease (CD) is strongly associated with the HLA alleles B8 and DR3, the genetic basis of this illness remains obscure. Recent studies show that at least two unlinked loci are involved. Most studies agree on recessivity at the HLA-unlinked locus but differ with respect to dominance or recessivity at the HLA-linked disease susceptibility locus. To address this controversy, we examined the association of CD with HLA in 39 families from the West of Ireland. Previous studies have shown that the prevalence of CD and the frequencies of the HLA antigens associated with it are higher in this population than in most others. Analysis of the data revealed a significant excess of concordant sib-pairs with two HLA haplotypes in common and an excess of discordant pairs with no haplotype in common. Chi-square tests confirmed a highly significant association between HLA-B8 and CD. Both heterozygotes and homozygotes for B8 had a significantly increased risk of CD. The risk for homozygotes was slightly higher than for heterozygotes, although not significantly so. The segregation ratio for disease occurrence among sibs of probands was estimated to be 0.185 when neither parent is affected. We estimated a gene frequency of 0.003 for the disease allele (C) at the HLA-linked locus and of 0.648 for the disease allele (d) at the HLA-unlinked locus. Assuming that CCdd homozygotes are always affected and that only carriers of C who are homozygous dd can be affected, the disease was found to be completely penetrant in Ccdd heterozygotes. These results support dominance at the HLA-linked locus conferring susceptibility to CD. Possible reasons for the discrepancy between the West of Ireland and other populations are discussed.

Alleles↗
PubMed1991

Mechanism of calcium ionophore and phorbol ester-induced T-cell activation. Accessory cell requirement for T-cell activation.

We examined the role of monocytes in T-cell activation induced by phorbol myristate acetate (PMA) and calcium ionophore ionomycin. Depletion of monocytes from peripheral blood mononuclear cells (PBMC) was associated with the loss of interleukin-2 (IL-2) production, IL-2 receptor (IL-2R) expression and proliferation, in response to either PMA or ionomycin. Addition of monocytes to highly purified T cells resulted in the complete reconstitution of IL-2 production, IL-2R expression and proliferation by PMA-stimulated lymphocytes. Exogenous IL-2, but not interleukin-1 (IL-1), could reconstitute the T-cell responsiveness. Addition of monocytes to highly purified T cells stimulated with ionomycin resulted in partial reconstitution of IL-2 production, IL-2R expression and proliferation. Similarly, the addition of exogenous IL-2 to ionomycin-stimulated T cells only partially reconstituted the response compared with PBMC. These results suggest that monocyte-T-cell interactions contribute to IL-2 production and IL-2R expression and are crucial events for PMA-induced T-cell proliferation. With ionomycin, monocytes play a role, in part, in inducing IL-2 production, IL-2R expression and proliferation. However, IL-2 is not a sufficient signal to induce T-cell proliferative response to ionomycin, suggesting that an IL-2-independent mechanism may exist in ionomycin-induced T-cell proliferation.

Cell Division↗
PubMed1989

Antibodies to beta 2-microglobulin, the light-chain component of class I histocompatibility molecules, provide an activation signal to human lymphocytes.

Antibodies to beta 2-microglobulin (beta 2m), the light-chain component of class I histocompatibility antigens, provide a strong co-stimulatory signal to human lymphocytes in the presence of phorbol ester. This activation signal requires a high concentration of antibody, whereas the effect on responses to a mitogenic lectin is exclusively inhibitory over a broad dose range. A rabbit polyclonal and a mouse monoclonal antibody to beta 2m were similarly co-stimulatory. Antibody to beta 2m was co-stimulatory with phorbol ester, but not calcium ionophore, suggesting that class I antigens play a role in the initiation of the 'first' signal of a recently described two-signal model of lymphocyte activation.

Antibodies↗
PubMed1989

Mechanism of a lymphocyte abnormality associated with HLA-B8/DR3 in clinically healthy individuals.

An important unanswered question in clinical immunology is why the histocompatibility antigens HLA-B8/DR3 should be associated with at least nine quite different immune-mediated diseases. The purpose of this study was to examine the mechanism of an immunologic abnormality, commonly found in healthy individuals with HLA-DR3, that may reflect an immune defect predisposing to autoimmunity. Fourteen healthy subjects with HLA-DR3 had a proliferative response to a suboptimal concentration of PHA nearly eight-fold lower than that observed in 10 individuals without this HLA antigen. Impaired responsiveness to PHA was more strongly associated with HLA-DR3 than with HLA-B8. The IL-2 concentration in mitogen-stimulated cultures was similarly decreased in subjects with HLA-DR3 and was highly predictive of the proliferative response 24 h later (r = 0.82, P less than 0.0001). Inhibition of IL-2 utilization by anti-IL-2 receptor antibody indicated that the reduced IL-2 concentration reflects impaired lymphokine production rather than increased utilization. Expression of IL-2 receptors is decreased in these subjects, although the magnitude of their proliferative response is appropriate for the available lymphokine. These results indicate that impaired lymphocyte activation associated with HLA-DR3 reflects impaired IL-2 production and an abnormality of activation events preceding the production of this lymphokine.

Adult↗
PubMed1986

Alpha 1-antitrypsin phenotypes, including M subtypes, in pulmonary disease associated with rheumatoid arthritis and systemic sclerosis.

Alpha 1-antitrypsin is a glycoprotein that functions as the major protease inhibitor in human serum. Many genetic variants of alpha 1-antitrypsin can be detected by electrophoretic techniques. We used isoelectric focusing on ultrathin gels to determine the common M subtypes as well as other variants of alpha 1-antitrypsin in 62 white patients with rheumatoid arthritis (RA) and 51 white patients with systemic sclerosis (SSc). We found no increased prevalence of variant phenotypes in either disease group as a whole. In RA, however, the association between pulmonary interstitial fibrosis and alpha 1-antitrypsin variants was striking. Interstitial fibrosis was seen on chest roentgenogram in only 1 of 30 subjects apparently homozygous for M1 (the "wild type" or "normal" phenotype), compared with 13 of 32 patients with variant phenotypes. Seven of 15 patients with M1M2 (the most common variant phenotype) had pulmonary fibrosis. In contrast, there was no apparent association of variant phenotypes with pulmonary involvement in SSc. Our findings suggest a possible role of alpha 1-antitrypsin in the pathogenesis of interstitial fibrosis in patients with RA. The absence of such an association in SSc suggests that pulmonary involvement in these 2 rheumatic diseases may have different pathogeneses.

Aged↗
PubMed1986

Immune abnormalities associated with HLA-B8: lymphocyte subsets and functional correlates.

Mononuclear cell populations were enumerated in healthy young adults with or without the histocompatibility antigen HLA-B8. Mononuclear cell counts were lower in subjects with HLA-B8, as was reflected in lower absolute numbers of the cell subsets. When cell populations were compared as percentages of total mononuclear cells, subjects with HLA-B8 had significantly more B lymphocytes bearing IgM than did subjects without HLA-B8. The T4/T8 ratio was significantly increased in subjects with HLA-B8. due both to increases in OKT4+ cells and to decrease in OKT8+ cells. B-Lymphocyte function was compared in subjects with and without HLA-B8 by measuring pokeweed mitogen driven differentiation of B cells to IgM bearing blasts, and was significantly greater in subjects with HLA-B8. Subjects with HLA-B8. Subjects with HLA-B8 were also found to have decreased Con A-induced suppression. Alterations in lymphocyte subsets and lymphocyte functions may underlie the predisposition to autoimmunity associated with HLA-B8.

Adult↗
PubMed1985

A modified double antibody sandwich enzyme-linked immunosorbent assay for measurement of alpha-1-antitrypsin in biologic fluids.

Alpha-1-antitrypsin (alpha 1AT) is the major protease inhibitor in human serum, and plays an important role protecting tissues from potentially harmful enzymes released during inflammatory reactions. Proteolytic enzymes such as leukocyte elastase are usually released and inactivated locally at the site of inflammation, so there has been much recent interest in measuring local alpha 1AT concentrations in biologic fluids. In this study, we developed a modified double antibody sandwich enzyme-linked immunosorbent assay (ELISA) and used it to measure alpha 1AT concentrations in several biologic fluids. The assay was sensitive to as little as 20 ng/ml of alpha 1AT. Serum concentrations measured by the ELISA correlated well with levels determined by radial immunodiffusion (RID) and the ELISA was far more sensitive than RID. In synovial fluid, higher concentrations determined by the ELISA compared with RID probably reflect interference of diffusion of alpha 1AT in the RID gel by hyaluronic acid and protease-inhibitor complexes. Synovial fluid did not interfere with the detection of added alpha 1AT by ELISA, but it did reduce the amount detected by RID by about 30% in 2 fluids. In saliva, alpha 1AT concentrations of less than 1 microgram/ml were easily quantified. Bronchoalveolar lavage fluids have been extensively studied because of the important role of alpha 1AT in pulmonary inflammatory processes. We found concentrations of 1-3 micrograms/ml in most samples with our assay. These levels were comparable to those previously reported with assays that required up to 50-fold concentration of the fluid. Neither saliva nor bronchoalveolar fluid significantly interfered with detection by ELISA of added alpha 1AT. This modified double antibody sandwich ELISA may have broad applications for studies of the role of alpha 1AT in health and disease.

Body Fluids↗
PubMed1985

Surface markers of suppressor cells in the spontaneous immunodeficiency disease of senescent NZB/NZW F1 hybrid mice.

Aged NZB/NZW F1 hybrid (B/W) mice spontaneously develop severe immunodeficiency disease associated with worsening autoimmunity and malignancies of the immune system. The impaired immune response is mediated in part by markedly increased suppressor cell activity in the spleens of these animals. In male B/W mice, the suppressor cell is nonphagocytic, nonadherent to nylon wool columns and highly resistant to treatment with anti-Thy-1 + complement. We report here marked ablation of splenic suppressor activity by anti-Lyt-1.2 + complement and to a much smaller extent by anti-Ly-2.2. The suppressor activity is not affected by anti-IgM + complement. These data suggest that the suppressor cell activity in the spleens of aged male B/W mice are in the T cell line and may result from an underlying disorder of T cell maturation and differentiation.

Aging↗
PubMed1984

Specificity of immunosuppression by human alveolar cells.

To study their effect on T- and B-lymphocyte functions, we obtained human alveolar cells, predominantly macrophages, by bronchoalveolar lavage. The cellular target of suppression by alveolar cells of lymphoproliferation was defined by cell separation techniques. THe results indicate a direct effect on T cells by alveolar cells via a soluble mediator released from alveolar cells. In contrast to the profound suppression of mitogen-induced T-cell proliferation, no significant suppression by equivalent numbers of alveolar cells was observed in assays of B-lymphocyte function or in the interactions of helper and suppressor T cells with B lymphocytes. These observations are consistent with an immunoregulatory role for alveolar cells, most likely alveolar macrophages: inhibiting cell-mediated immune responses and delayed hypersensitivity in the lung, while favoring antibody responses.

B-Lymphocytes↗
PubMed1983

Surface properties of lymphocyte subpopulations in autoimmune NZB/NZW F1 hybrid mice: alterations correlated with the immunodeficiency of aging.

Partitioning in a two-polymer aqueous phase system was used to probe the surface properties of lymphoid cell subpopulations in aged male NZB/NZW F1 hybrid (B/W) mice, an important model of autoimmunity, immunodeficiency, and lymphoid malignancy. Spleen cells were fractionated by countercurrent distribution (CCD, a multiple-step extraction procedure) in a charged dextran-polyethylene glycol system. CCD of spleen cells from young, clinically normal male B/W mice yielded several broad distribution patterns which frequently had two or more peaks. Analysis of differentiation antigens and functional properties of cells from different parts of the distribution revealed a subfractionation of the three major lymphocyte subpopulations. B lymphocytes had a low partition coefficient (K); T cells had an intermediate K and null cells had the highest K. To examine the partitioning behavior of T lymphocytes, spleen cells which were nonadherent to nylon wool columns were subjected to CCD. Nonadherent cells from young B/W mice consistently gave a single peak with high K. Aged mice (18 months) usually had nonadherent cells with a predominantly low K. In some experiments a systematic increase in the number of these cells could be demonstrated with increasing mouse age. An analysis of the adherence and partitioning behavior of lymphocyte subpopulations revealed no change in the adherence properties or proportions of B lymphocytes in aged mice. The large proportion of cells having a low partition coefficient in the nonadherent spleen cell population of old mice appears to be due to an increase in the number of null cells and in a decrease in the K of some T lymphocytes.

Aging↗