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Biomedical subjects

S Whittingham

Publications and source records attributed to S Whittingham.

At least 55 records · Page 3Linked to original sources
PubMed1984

A strong association between the antinuclear antibody anti-La (SS-B) and the kappa chain allotype Km(1).

The distribution of immunoglobulin allotypes of the Gm and Km systems was examined in 51 patients with antinuclear antibodies (ANA), which reacted with two saline-extractable non-DNA nuclear antigens, anti-La (SS-B) and anti-RNP, which characterize certain multisystem autoimmune diseases. Forty-six percent of the 26 patients with anti-La were positive for the Km(1) allotype compared with 14% of the 35 with anti-RNP and 16% of 1204 of healthy subjects (corrected P value less than 0.005). The high frequencies of the Km(1) allotype (46%), female sex (100%), and the HLA-B8, DR3 phenotype (greater than 90%) in patients with anti-La are indicative of a substantial inherited predisposition to the development or expression of this autoantibody. The strong association between the Km(1) allotype and the anti-La response may be due to linkage disequilibrium between genes coding for the constant region of immunoglobulin kappa light chains and genes coding for the variable regions of kappa light chains which confer antibody specificity for the special configuration of the ribonucleoprotein known as La.

Antibodies, Antinuclear↗
PubMed1984

Autoantibodies reactive with small ribonucleoprotein antigens: a convergence of molecular biology and clinical immunology.

Autoantibodies to nuclear antigens (ANA) occur in patients with systemic lupus erythematosus (SLE) and other multisystem autoimmune diseases. Although heterogeneous, there are 2 major groups, autoantibodies to DNA and autoantibodies to non-DNA antigens, the latter including ANAs to the soluble or "extractable nuclear antigens" (ENA). This review discusses those ENAs which are ribonucleoproteins (RNPs) consisting of small RNA molecules (80-400 nucleotides) attached to non-histone proteins: these are called small nuclear (sn) or small cytoplasmic (sc) ribonucleoproteins according to their location in the cell and at least some are known to play an important role in nuclear metabolism. ENAs can be immunoprecipitated from crude preparations of nuclei by sera from patients with multisystem autoimmune diseases and, after removal of the associated proteins, the RNA components can be analyzed by gel electrophoresis. This shows 3 main categories of small RNAs: the U group comprising U1-U6 snRNAs, the Ro group comprising small nucleocytoplasmic RNAs, and the La group comprising several species of cellular snRNAs as well as the Ro scRNAs. La, in addition, includes small RNAs encoded by adenovirus (VA I, VA II), Epstein-Barr virus (EBER 1, EBER 2) and vesicular stomatitis virus (leader RNA). In the case of each group, the RNAs themselves are not antigenic but become so when associated with proteins, most of which are uncharacterized. The U snRNAs, located in the nucleus, are transcribed by RNA polymerase II and appear to be involved in the splicing of introns from mRNA. Sera from patients with mixed connective tissue disease (MCTD) react with RNPs containing U1 RNA and sera from patients with SLE react with U RNPs containing U1, U2, U4, U5 and U6 RNAs, collectively known as the Sm antigen. The Ro RNAs are transcribed by RNA polymerase III and have no known function. Sera from patients with primary Sjögren's syndrome and some cases of SLE react with Ro scRNPs. The La RNAs are also transcribed by RNA polymerase III and are located mostly in the nucleus; functionally the protein associated with the La RNAs appears to be important in RNA polymerase III transcription. Sera from patients with primary Sjögren's syndrome react with the heterogeneous group of both cellular and viral RNAs which constitute the La RNP antigen. Sera of patients with SLE, scleroderma, polymyositis and dermatomyositis also react with RNPs relevant to nuclear metabolism and further definition of these RNPs is awaited. Many advances can be expected from the convergence of molecular biology and clinical immunology exemplified by the current studies on ENAs.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Antinuclear↗
PubMed1983

A solid phase radioimmunoassay for detection of antibodies to extractable nuclear antigens.

A solid phase radioimmunoassay is described for the detection of autoantibodies to the saline-soluble extractable nuclear antigens, ribonucleoprotein (RNP) and SS-B (or La). This assay depends on enrichment of antigens from a crude, commercially available (Pel Freez, U.S.A.) extract of rabbit thymus by absorption to the F(ab)2 fraction of specific high titre antibody attached to a microtitre plate. Serum antibody reactive with this antigen is then detected by 125I-labelled Protein A. The assay is simple and is more sensitive than the gel diffusion assays in general use for detecting such antibodies.

Antibodies↗
PubMed1983

HLA and Gm genes in systemic lupus erythematosus.

HLA and Gm phenotypes were compared in 53 patients with unequivocal systemic lupus erythematosus (SLE) and in 180 healthy subjects. SLE was associated with HLA-B8 (relative risk (RR) = 3.5, P less than 0.001) and with HLA-DR3 (RR = 2.8, P less than 0.01). There was an increased risk of SLE with HLA-B8/B27 (RR = 27.6) and with HLA-B15/B35 (RR greater than 13) and, in contrast, the risk was decreased in subjects with HLA-B40 (RR = 0.3). The risk of SLE in subjects who were heterozygous for the Gm phenotypes a,f,x; b,g was increased (RR = 2.0, P = 0.03) relative to the risk in subjects who were homozygous for these Gm phenotypes. These findings suggest that susceptibility to SLE is influenced by one or more genes in linkage disequilibrium with the HLA-B8-DR3 haplotype, by "augmentor" or "protector" genes associated with other HLA antigens and by separate genes, possibly VH genes, in linkage disequilibrium with the Gm (CH allotype) locus.

Genes, MHC Class II↗
PubMed1983

Autoantibodies to small nuclear ribonucleoproteins. A strong association between anti-SS-B(La), HLA-B8, and Sjögren's syndrome.

The heterogeneity within multisystem autoimmune disease was evaluated according to the presence of antinuclear antibodies to ribonucleoproteins and the HLA-A1, B8, DR3 phenotype. Patients with various multisystem autoimmune diseases were tested by a highly sensitive radioimmunoassay for autoantibodies to the small nuclear ribonucleoproteins known as SS-B (La) and ribonucleoprotein (RNP), and HLA phenotypes were determined. The 210 patients included 64 with systemic lupus erythematosus (SLE), 11 with "atypical SLE", 41 with Sjögren's syndrome, 22 with mixed connective tissue disease (MCTD), 21 with rheumatoid arthritis (RA), 16 with primary biliary cirrhosis (PBC) and 35 with autoimmune chronic active hepatitis (A-CAH). Anti-SS-B (La) was present in high frequency in Sjögren's syndrome and was strongly associated with HLA-A1, B8, DR3. Anti-RNP was detected predominantly in MCTD and had no association with HLA-A1, B8, DR3. There were sharply defined serological and genetic differences between primary Sjögren's syndrome and Sjögren's syndrome associated with RA. Anti-SS-B (La) was present in 70% of patients with primary Sjögren's syndrome but in none with Sjögren's syndrome with RA, and the respective frequencies of HLA-A1, B8, and DR3 were 88%, 94% and 75% in the former compared with 38%, 29% and 14% in the latter. Thus primary Sjögren's syndrome differs immunogenetically from Sjögren's syndrome with RA. There was a notable absence of anti-SS-B (La) in PBC, an autoimmune disease associated with the Sjögren's syndrome. These findings illustrate the value of studying immunological and genetic markers in detecting heterogeneity within groups of diseases whose symptoms cannot be distinguished clinically.

Antibodies, Antinuclear↗
PubMed1983

Strain differences in mice in carbon tetrachloride-induced liver injury.

A study was made in inbred mice of genetic determinants of toxic liver cell injury, and the subsequent occurrence of autoantibodies to mouse liver-specific protein (M-LSP). Carbon tetrachloride was injected s.c. in sublethal doses to induce liver cell damage in 4 strains of mice, BALB/c, C3H, C57BL/6 and SJL/J. The degree of liver cell damage was assessed by blood cholylglycine levels and by semiquantitative histological analysis 1, 4, 7, 14, 21 and 45 days after dosing. Striking differences were observed among the 4 strains in degrees of liver necrosis, cellular infiltration and rate of removal of the necrotic tissue. BALB/c was the strain most susceptible to the necrotizing effects of CCl4. These mice showed confluent areas of hepatocellular necrosis from Day 1 and histological recovery was protracted up to 3 weeks, and was accompanied by pronounced macrophage activity and a cellular inflammatory response. Mice of the SJL/J strain were the least susceptible and showed minor hepatocellular necrosis, which resolved by Day 7, and a slight histiocytic response. C3H and C57BL/6 showed lesions which were intermediate between the other 2 strains. The autoantibody response to LSP was weak, transient and detected only in C57BL/6 mice. This study indicates the presence of genetic control, either H-2 or non-H-2 linked, over the degree of liver cell necrosis resulting from toxic liver injury, and the ensuing cellular infiltrate and rate of removal of the necrotic tissue.

Animals↗
PubMed1982

Use of tetanus toxoid for testing cell-mediated immunity.

Tetanus toxoid was assessed as a skin test antigen for the measurement of cutaneous delayed-type hypersensitivity (DTH) by comparing the responses to intradermal injections of aqueous tetanus toxoid and an extract of Candida albicans in 50 randomly selected healthy adults and 10 adults with immunodeficiency. Of 42 healthy subjects previously immunised with tetanus toxoid, 33 (79%) reacted to tetanus toxoid and 33 (79%) reacted to Candida albicans. Of eight non-immunised subjects, none reacted to tetanus toxoid although five reacted to Candida albicans. Ten immunodeficient adults previously shown to be anergic to a standard panel of five skin test antigens including Candida albicans, and who had received primary immunisation and booster doses of tetanus toxoid, were anergic on current testing with tetanus toxoid and Candida albicans. Tetanus toxoid in previously immunised subjects has certain advantages as a "recall" DTH test antigen over the standard skin test antigens candidin, mumps, trichophyton, tuberculin and streptokinase-streptodornase used to diagnose cell-mediated immuno-deficiency. It is a sensitive measurement of DTH, it recalls a defined immunological event, it has a low incidence of side effects, and it produces a slight but beneficial boosting of serum antibody to tetanus toxoid.

Adenocarcinoma↗
PubMed1982

Autoimmunity in the Lambert-Eaton myasthenic syndrome.

Sera from 64 patients with the Lambert-Eaton myasthenic syndrome (LES) were tested for evidence of autoimmunity to a variety of tissue antigens. One or more organ-specific autoantibodies (thyroid, gastric, and/or skeletal muscle) were found in 29 patients (45%). Of 46 patients without evidence of tumor, autoantibodies were found in 24 (52%), and of 18 patients with tumor, autoantibodies were found in 5 (28%). In an age-matched group of 40 patients with miscellaneous neurologic diseases, 7 (17%) had one or more organ-specific autoantibodies, and in a control group of 47 patients with myasthenia gravis the combined prevalence of thyroid and gastric antibodies was 47%, comparable to that found in LES patients. The prevalence of non-organ-specific autoantibodies (for example, rheumatoid factor and/or antinuclear antibodies) was not significantly elevated in LES. These data clearly justify consideration of LES without tumor as an organ-specific autoimmune disease. If LES with tumor does prove to have an autoimmune basis, the mechanism may involve an antigen common to cholinergic neurons and oat cell carcinoma, both of which are neuroectoderm derivatives.

Adenocarcinoma↗
PubMed1981

An autoantibody reactive with nuclei of polymorphonuclear neutrophils: a cell differentiation marker.

An autoantibody that reacted with nuclei of polymorphonuclear neutrophils (PMN) was detected at titers of greater than 10 in sera of 25 of 50 patients with rheumatoid arthritis and 36 of 50 with autoimmune chronic active hepatitis but in none of 160 controls comprising 24 patients with alcoholic cirrhosis, 36 with multiple myeloma, and 100 healthy subjects. Through the use of enriched populations of hemopoietic cells, this antibody was shown to be cell-specific, reacting only with the nucleus of the mature neutrophil. It was unreactive with nuclei of progenitor cells in the myeloid series and with nuclei of eosinophils, monocytes, lymphocytes, and thymocytes. It reacted with a determinant that appeared to be a differentiation antigen. This cell-specific autoantibody may prove to be of value in analytical studies of granulocyte maturation.

Antibodies, Antinuclear↗
PubMed1981

Interaction of HLA and Gm in autoimmune chronic active hepatitis.

An immunogenetic study of autoimmune chronic active hepatitis (CAH) showed the relative risk (RR) for this disease was 11.6 for patients who were HLA-B8, 11.7 for patients who were DR3 and 2.3 for patients who were Gma+x+. Moreover, the Gm haplotype Gma+x+ was present in 18 of 40 (45%) patients with HLA-B8, but in none of 10 patients negative for HLA-B8, whereas in 180 healthy controls Gma+x+ was evenly distributed among those positive (24%) and negative (18%) for HLA-B8. The RR was lowest in patients lacking HLA-B8 but positive for Gma+x+. Relative to this low-risk group, the risk was increased 39 times in subjects with both HLA-B8 and Gma+x+, 15 times in subjects with HLA-B8 who were not Gma+x+ and twice in subjects who were neither HLA-B8 nor Gma+x+. Statistical analysis indicated that the three-factor effect (disease risk affected by non-additive effects of HLA-B8 and Gma+x+) was significant (P less than 0.01), as were the main effects of HLA-B8 (P less than 0.001) and Gma+x+ (P less than 0.02). Thus in the presence of HLA-B8, genes linked to Gma+x+, an immunoglobulin CH allotype, may contribute to the development of autoimmune chronic active hepatitis; in the absence of HLA-B8 these same genes appear to be inactive. This may indicate interactions between MHC gene products and VH gene products in the presentation and recognition of autoantigen(s) in autoimmune hepatitis.

Autoimmune Diseases↗
PubMed1980

Diagnostic significance of thyroid microsomal antibodies in randomly selected population.

A longitudinal study among the population of Busselton, Western Australia, has identified individuals with persistent and transient thyroid microsomal antibodies (TMA). 59 (72%) of 82 subjects with persistent TMA, 18 (72%) of 25 with recently developed TMA, and 12 (23%) of 53 with transient antibody were found to have subclinical hypothyroidism, as indicated by high serum thyroid stimulating hormone concentrations. This study reveals the high specificity, sensitivity, and predictive value of persistent or recently required TMA.

Adult↗
PubMed1980

Interactive effect of Gm allotypes and HLA-B locus antigens on the human antibody response to a bacterial antigen.

Two hundred healthy adults were immunized with 1 microgram of the bacterial antigen monomeric flagellin from Salmonella adelaide, and grouped as responders and non-responders on the basis of a rise in titre of antibody 2 weeks after immunization. Immunoglobulin allotypes G1m(a), G1m(z) and G3m(g) were more frequent among responders who made immunoglobulin (Ig)G antibody (P less than 0.02), and HLA-B12 was more frequent among responders who made IgM antibody (P less than 0.05). The mean log titre of IgG antibody was higher in females (P less than 0.001), in subjects with T1m(a), G1m(z) and G3m(g) allotypes (P less than 0.05), and in Gm heterozygotes (P less than 0.01). The mean log titre of the IgG antibody response in subjects with particular Gm phenotypes was also dependent on the HLA-B locus phenotypes HLA-B7, B8 and B12 (P less than 0.005); for example, among those with the phenotype Gm(a-x-b) subjects with HLA-B7 were low responders and those with HLA-B8 were high responders. These findings are consistent with the hypothesis that there are immune response genes within the major histocompatibility complex (MHC) which interact with Gm-linked genes in determining levels of serum antibodies of different isotypes and specificities.

Adolescent↗
PubMed1980

A population survey of pancreatic islet cell antibodies.

A population study on pancreatic islet cell antibodies (pica) among 3766 people from the town of Busselton, Western Australia showed that such antibodies were infrequent, the 'classical' insulin-dependent diabetes associated islet cell antibody being present in less than 0.01%. Pancreatic islet cell antibodies in this population were not associated with insulin-dependent diabetes mellitus, and ten known insulin-dependent diabetics did not have these antibodies. These results for an unselected population are in sharp contrast with those derived from studies on highly selected hospital patients.

Adolescent↗
PubMed1979

Impairment of Jones-Mote hypersensitivity and specific antibody response against depolymerized flagellin in lepromatous leprosy.

Cutaneous hypersensitivity and antibody-producing capacity were assessed in patients with lepromatous leprosy with defective immunity, by immunizing them with monomeric flagellin from Salmonella adelaide. Results were compared with those of controls, matched for age and sex, derived from similar socioeconomic stratum, but without any defect of the immunological system. In contrast to the normal individuals, who showed Jones-Mote type of hypersensitivity, no lepromatous patient could mount any 'delayed-in-time' cutaneous hypersensivivity reaction against an intradermal challenge of monomeric flagellin. However, when immunized through the subcutaneous route, both groups could produce adequate amounts of specific serum antibody. In addition to this unique split tolerance found in all lepromatous patients, some patients showed low levels of 'natural' IgM antibody, reduced formation of specific antibody when immunized through the subcutaneous route, and incomplete maturation of IgG class of anti-flagellin antibody. When immunized by the intradermal route, however, production of both anti-flagellin antibody and maturation of IgG antibody was significantly inhibited in normal adults but not in lepromatous patients. Thus, contrary to the earlier concept of hyperactivity of the humoral immune apparatus in lepromatous leprosy, the present study detected B-cell hypofunction in some patients.

Adult↗