Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. The Multiple Sclerosis Genetics Group

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system. While its etiology is not well understood, genetic factors are clearly involved. Until recently, most genetic studies in MS have been association studies using the case-control design testing specific candidate genes and studying only sporadic cases. The only consistently replicated finding has been an association with the HLA-DR2 allele within the major histocompatibility complex (MHC) on chromosome 6. Using the genetic linkage design, however, evidence for and against linkage of the MHC to MS has been found, fostering suggestions that sporadic and familial MS have different etiologies. Most recently, two of four genomic screens demonstrated linkage to the MHC, although specific allelic associations were not tested. Here, a dataset of 98 multiplex families was studied to test for an association to the HLA-DR2 allele in familial MS and to determine if genetic linkage to the MHC was due solely to such an association. Three highly polymorphic markers (HLA-DR, D6S273 and TNFbeta) in the MHC demonstrated strong genetic linkage (parametric lod scores of 4.60, 2.20 and 1.24, respectively) and a specific association with the HLA-DR2 allele was confirmed (TDT; P < 0.001). Stratifying the results by HLA-DR2 status showed that the linkage results were limited to families segregating HLA-DR2 alleles. These results demonstrate that genetic linkage to the MHC can be explained by the HLA-DR2 allelic association. They also indicate that sporadic and familial MS share a common genetic susceptibility. In addition, preliminary calculations suggest that the MHC explains between 17 and 62% of the genetic etiology of MS. This heterogeneity is also supported by the minority of families showing no linkage or association with loci within the MHC.      

Streptococcus pyogenes infection in mouse skin leads to a time-dependent up-regulation of protein H expression

Streptococcus pyogenes protein H (sph) is an immunoglobulin-binding protein present in the Mga regulon of certain M1 serotype isolates. Although sph is present in many strains, it is frequently not expressed. In this paper we show that protein H was highly expressed after bacteria were injected into the skin of mice and were recovered from the blood, kidney, or spleen at various times postinfection. The percentage of protein H-positive colonies increased with time, reaching 100% in the spleen and kidney within 24 to 72 h postinfection. The up-regulation of sph expression was also observed in a mga mutant.     

Comparison of field and vaccine strains of Australian fowlpox viruses

Summary. The mild fowlpox vaccine, FPV M, widely used in Australia is composed of two predominant genotypes based upon differences identifiable in restriction enzyme analyses of plaque purified derivatives of this vaccine. The differences, where identifiable, were in the end fragments of the genomes. Five field isolates of FPV from chickens in New South Wales showed restriction enzyme profiles closely related to the more virulent (standard) vaccine strain, FPV S. The FPV S strain differs from FPV M in both terminal genome fragments and in the presence of a PstI fragment of approximately 10kb (this fragment was also present in PstI digests of all of the field isolates). Plaque purified derivatives of FPV M showed similar lesion development upon inoculation into the wing web of chickens. The field isolates showed significantly higher virulence in day-old and three-week-old chickens in comparison with FPV M. One field isolate was similar to the FPV S vaccine. Two isolates had slowly developing wing web lesions, caused significant secondary lesions in three-week-old chickens and generalised poxvirus infection when inoculated into day-old chickens. For two isolates, the primary wing web lesion took even longer to develop and resolve although these isolates did not cause generalised poxvirus infection. It was possible to identify four virulence/pathogenicity types amongst these vaccine and field isolates of FPV. These strains may allow the characterisation of FPV encoded virulence factors. The field strains with higher virulence may be suitable as parent strains for the construction of FPV recombinants with enhanced immune responses to co-expressed vaccine antigens when compared with current FPV M strain based recombinants. Received July 19, 1996 Accepted September 26, 1996     

Identification of non-immunoglobulin A-Fc-binding forms and low-molecular-weight secreted forms of the group B streptococcal beta antigen.

The beta antigen expressed on the surfaces of certain strains of group B streptococci has been reported to bind to the Fc region of human immunoglobulin A (IgA). In this study, we screened 100 isolates of group B streptococci for expression of both beta antigen and IgA-Fc-binding activity. We identified two isolates which expressed the beta antigen but could not bind human IgA Fc fragments and also observed variability in IgA-Fc-binding activity among other beta-antigen-expressing strains. Novel low-molecular-weight forms of beta antigen were secreted by four beta-antigen surface-negative isolates and included IgA-Fc-binding (Mrs, 55,000 and 53,000) and non-IgA-Fc-binding (Mr, 38,000) molecules. These results suggest that the IgA-Fc-binding site represents a unique domain of the beta antigen. The 55,000- and 53,000-Mr forms of secreted beta antigen were functionally and antigenically representative of the size-heterogeneous (Mr, up to 145,000) beta-antigen molecules expressed by surface-positive strains. The cell surface-localized IgA-Fc-binding molecules could bind only human serum IgA efficiently; however, once solubilized, these molecules could bind both human serum and secretory IgAs.     

Plasma immunoglobulin concentrations in twins

A study has been made of the similarity of concentrations of IgG, IgA and IgM in twins. The results provide evidence for the genetic control of all three immunoglobulins in adolescence, but in adults genetic control was demonstrable only for IgG in males. The findings suggest that although genetic factors regulating all classes of immunoglobulin levels in adults cannot be excluded by this study, if such factors do exist their effects are relatively small or are confined to certain individuals. This conclusion suggests that immunoglobulin concentrations in healthy adults will not form useful indices of future susceptibility to genetically determined diseases of immunity.     

Malignant fibrothecomatous tumour of the ovary: diagnostic value of anti-inhibin immunostaining

Malignant ovarian tumours of the fibrothecoma group are rare. The clinicopathological features of a case of ovarian malignant fibrothecoma in which there was metastatic disease in the small intestine and peritoneum at presentation are described. A number of differential diagnoses were considered but positive immunohistochemical staining of the resected ovarian and small intestinal neoplasms with anti-inhibin was of value in confirming a sex cord-stromal tumour and in excluding other lesions. The two tumours were also ultrastructurally identical. Classical malignant fibrothecomas are said to show four or more mitotic figures per 10 high power fields (HPF). Although the intestinal secondary was mitotically active, the primary ovarian tumour contained only one to two mitoses per 10 HPF, showing that formal mitotic counts are not an absolute indicator of malignant behaviour in this group of tumours.     

Conjugal prevalence of rheumatoid arthritis, rheumatoid factor and other autoantibodies in rheumatoid arthritis

The prevalence of rheumatoid arthritis, rheumatoid factor, antinuclear autoantibodies, thyroglobulin and thyroid `microsomal'' autoantibodies and gastric parietal cell autoantibodies has been studied in 327 husbands and 181 wives of 508 probands with seropositive `definite'' or `classical'' rheumatoid arthritis as defined by the American Rheumatism Association diagnostic criteria. Two husbands and three wives had definite rheumatoid arthritis: this prevalence is no higher than one might expect. A higher prevalence of all five autoantibodies was found in husbands compared with age matched controls, but only in respect of antinuclear autoantibodies and thyroglobulin autoantibody were the differences statistically significant. In the wives only rheumatoid factor showed a significantly higher prevalence as compared with controls. The presence of autoantibodies in husbands and wives showed no relationship to the duration of marital contact nor to the presence of the autoantibodies in the probands. The prevalence of autoantibodies in spouses of probands who developed their arthritis after marriage showed no difference when compared with that in probands who developed their arthritis before marriage.