Autoantibodies to fibrillin-1 (Fbn-1) have been found in systemic sclerosis (SSc), calcinosis, Raynaud's esophagael dysmotility, sclerodectyly, and telaengectasia (CREST) and mixed connective tissue disease (MCTD) diseases. The purpose of this study was to determine whether patients with primary pulmonary hypertension (PPH) and appetite-suppressant-associated PPH have anti-Fbn-1 autoantibodies. In addition we assessed the human leucocyte antigen (HLA) class II alleles (DRB1, 3, 4, 5 and DQB1) in these patients in order to determine whether the response is genetically restricted. The frequency of anti-Fbn-1 autoantibodies in patient groups was compared with that of a control group of 88 healthy patients, and HLA was correlated similarly with a group of 51 healthy subjects. Anti-Fbn-1 autoantibodies were found at high frequency in PPH: in 70 of 75 adults with PPH (93%), in 28 of 33 children with PPH (84.8) and in 12 of 18 (67%) patients with appetite-suppressant-associated PPH. Utilization of two Fbn-1 fusion proteins allowed us to determine the dominant determinant region, recognized by anti-Fbn-1 autoantibodies, which may be located on the N-terminal fragment of the Fbn-1 protein. No significant immunogenetic correlations were found when the PPH patient groups were compared with normal controls. This novel category of autoantibodies is found in diseases characterized by endothelial and extracellular matrix protein alterations and fibrosis.

Studies carried out during the past decade suggest that the tight skin (TSK) mouse represents an excellent experimental model for human scleroderma'~* and congenital fascia1 dy~trophy.~ TSK syndrome is due to an autosomal dominant mutation located on chromosome 2 at about 2 cm distal to the pallid mutation, close to p2 microglobulin, ILla, and fibrillin-1 In homozygous state, the mutants die in utero. The TSK syndrome is characterized by cutaneous hyperplasia, tightness of the skin, cardiac hypertrophy, pulmonary emphysema, and hypertrophy of the ~keleton.~ The histopathological alterations seen in the skin are due to an increase in the expression of type I and III procollagen genes,5 excessive accumulation of colIagens,6 glycosamin~glycans,~ and increased propyl hydroxylase enzyme activity.* Human scleroderma is a polymorphic disease manifested as localized scleroderma (morphea) progressive systemic sclerosis (PSS) or as CREST syndrome. All these syndromes are associated with the production of autoantibodies displaying a variety of specificities against cellular autoantigens. Our studies were aimed at characterizing the autoantibodies associated with tight skin syndrome, as well as determining their pathogenic properties.

Mice carrying the tight skin (TSK) mutation harbors a 3.0-kb genomic duplication (exons 17-40) of the fibrillin-1 gene (Fbn-1) located on band F of chromosome 2 as TSK mutation. We cloned and sequenced the mutated Fbn-1 gene, since it is believed to be responsible for TSK syndrome. Sequence analysis showed numerous amino acid differences in the 5' and 3' segments between the TSK mutation and wild-type fbn-1 gene, but any amino acid difference between the TSK mutation and C57BL/6 mice. (TSK and C57B1/6 mice are genetically similar, differing only by TSK mutation.) Four amino acid differences were observed between two copies of TSK's fbn-1 gene encoded by exons 17-40. Our results suggest that the majority of structural differences occurred in the N and C termini segments during strain divergence and only a few after the duplication event.

Several hundred hybridomas were obtained from 1-2-mo-old viable motheaten (mev) mice. Among the Ig-secreting hybridomas tested, greater than 50% (17/33) exhibited reactivity for autoantigens, supporting the idea that the Ly-1 B cells that predominate in mev mice contain frequent precursors of autoantibody-forming cells. Certain of the specificities of these autoantibodies correlated with the documented pathophysiology of mev mice (antithymocyte, -erythrocyte, -skin, -kidney, and -IgG); others were specific for autoantigens not previously observed in motheaten mice but though to be involved in other autoimmune diseases (e.g., intrinsic factor, transferrin, myelin basic protein, and thyroglobulin). About 2 of 3 (11/17) of the self-reactive antibodies exhibited multispecific binding activity for various autoantigens. Analysis by Northern blotting of the V gene families used in mev autoantibodies showed a random usage of VH families and a biased usage of four Vk gene families. Of 16 autoantibodies tested, 12 used a Vk gene from the Vk1, 4, 10, or 19 families. These patterns of Vk gene usage differ from nonautoimmune control animals. Overall, an immunoregulatory defect operating at a more generalized level than the VH or Vk loci, and due to a single gene mutation, appears to be responsible for the multiple immune abnormalities of mev mice.

Annals of the New York Academy of SciencesVolume 546, Issue 1 p. 210-213 Biased Use of Certain Vk Gene Families by Autoantibodies R. MAYER, R. MAYER Mount Sinai School of Medicine New York. New York 10029Search for more papers by this authorV. FIDANZA, V. FIDANZA Mount Sinai School of Medicine New York. New York 10029Search for more papers by this authorK. KASTURI, K. KASTURI Mount Sinai School of Medicine New York. New York 10029Search for more papers by this authorC. A. BONA, C. A. BONA Mount Sinai School of Medicine New York. New York 10029Search for more papers by this author R. MAYER, R. MAYER Mount Sinai School of Medicine New York. New York 10029Search for more papers by this authorV. FIDANZA, V. FIDANZA Mount Sinai School of Medicine New York. New York 10029Search for more papers by this authorK. KASTURI, K. KASTURI Mount Sinai School of Medicine New York. New York 10029Search for more papers by this authorC. A. BONA, C. A. BONA Mount Sinai School of Medicine New York. New York 10029Search for more papers by this author First published: December 1988 https://doi.org/10.1111/j.1749-6632.1988.tb21642.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume546, Issue1Molecular Basis of the Immune ResponseDecember 1988Pages 210-213 RelatedInformation

Of 79 hybridomas derived from stimulated or unstimulated autoimmune disease prone mouse strains, secreting autoantibodies of various specificities more than 65% use V genes from five Vk families, namely, Vk1, Vk4, Vk8, Vk10 and Vk19. Restriction fragment length polymorphism (RFLP) analysis of genomic DNAs from autoimmune prone mouse strains, tight skin, NZB and SJL show marked differences in the polymorphism of the Vk1, Vk10 and Vk19 gene families.