The long term major objectives of this application are to analyze in detail the major histocompatibility complex genes in ocular cicatricial pemphigoid (OCP). We hope to identify susceptibility genes that are associated with the production of anti-basement membrane zone (BMZ) antibodies. Our preliminary studies indicate a strong association between B44, DR4, DQw3 in OCP. Furthermore, we have developed a radioimmunoassay to detect anti-BMZ antibodies present in very low titers. Our studies in pemphigus indicate that the ability to produce autoantibodies may be linked to MHC genes, and family members that carry the """"""""disease-bearing"""""""" haplotype often have very low titers of pemphigus antibodies. We propose to do complete HLA studies in OCP patients, in order to test the hypothesis that the haplotype (only the phenotypes have so far been studied) B44, DR4, DQw3 together with other Class II alleles and complotypes carry a susceptibility gene for anti-BMZ antibody production and OCP. Nucleotide sequencing of the regions (DQ, DR) carrying the susceptibility gene(s) will be done to determine if there are any amino acid differences between the individuals with and without the anti-BMZ antibody, but have the same extended haplotype or portions of it. Furthermore, comparison of the DR4 of that extended haplotype of OCP patients with other DR4-associated haplotypes, will be very helpful in determining if the DR4 molecule is directly involved in the pathogenesis of OCP. Molecular probes will be used in analyzing in detail the genes associated with OCP and/or anti-BMZ antibody production in an effort to identify disease-specific restriction fragment length polymorphism. These studies are possible because Dr. Stephen Foster of the Mass Eye & Ear Infirmary has 130 patients with OCP. Seventy patients with OCP have been recently studied. Dr. Ahmed is a dermatologist with interest in the immunogenetics of blistering diseases. Dr. Ahmed has the collaboration of two immunogeneticists (Dr. Alper and Dr. Yunis) who will not only provide Dr. Ahmed with the necessary environment and advice to perform and analyze these experiments, but actively participate in the project. Thus the proposal will help in significantly advancing our ability to localize a susceptibility gene for OCP and to study the genetic control of anti-BMZ antibody production.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY008379-02
Application #
3265677
Study Section
Visual Sciences A Study Section (VISA)
Project Start
1990-01-01
Project End
1992-12-31
Budget Start
1991-01-01
Budget End
1991-12-31
Support Year
2
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Immune Disease Institute, Inc.
Department
Type
DUNS #
115524410
City
Boston
State
MA
Country
United States
Zip Code
02115
Razzaque, Mohammed S; Ahmed, Babar S; Foster, C Stephen et al. (2003) Effects of IL-4 on conjunctival fibroblasts: possible role in ocular cicatricial pemphigoid. Invest Ophthalmol Vis Sci 44:3417-23
Razzaque, Mohammed S; Foster, C Stephen; Ahmed, A Razzaque (2003) Role of connective tissue growth factor in the pathogenesis of conjunctival scarring in ocular cicatricial pemphigoid. Invest Ophthalmol Vis Sci 44:1998-2003
Bhol, K C; Colon, J E; Ahmed, A R (2003) Autoantibody in mucous membrane pemphigoid binds to an intracellular epitope on human beta4 integrin and causes basement membrane zone separation in oral mucosa in an organ culture model. J Invest Dermatol 120:701-2
Razzaque, Mohammed S; Foster, C Stephen; Ahmed, A Razzaque (2002) Role of enhanced expression of m-CSF in conjunctiva affected by cicatricial pemphigoid. Invest Ophthalmol Vis Sci 43:2977-83
Colon, J E; Bhol, K C; Razzaque, M S et al. (2001) In vitro organ culture model for mucous membrane pemphigoid. Clin Immunol 98:229-34
Kumari, S; Bhol, K C; Simmons, R K et al. (2001) Identification of ocular cicatricial pemphigoid antibody binding site(s) in human beta4 integrin. Invest Ophthalmol Vis Sci 42:379-85
Kumari, S; Bhol, K C; Rehman, F et al. (2001) Interleukin 1 components in cicatricial pemphigoid. Role in intravenous immunoglobulin therapy. Cytokine 14:218-24
Engineer, L; Bhol, K; Kumari, S et al. (2001) Bullous pemphigoid: interaction of interleukin 5, anti-basement membrane zone antibodies and eosinophils. A preliminary observation. . Cytokine 13:32-38
Bhol, K C; Goss, L; Kumari, S et al. (2001) Autoantibodies to human alpha6 integrin in patients with oral pemphigoid. J Dent Res 80:1711-5
Bhol, K C; Dans, M J; Simmons, R K et al. (2000) The autoantibodies to alpha 6 beta 4 integrin of patients affected by ocular cicatricial pemphigoid recognize predominantly epitopes within the large cytoplasmic domain of human beta 4. J Immunol 165:2824-9

Showing the most recent 10 out of 40 publications