The objectives of this research program are to define the basic immunology of the serum IgA immune system, with particular attention to its role as an orchestrator and modulator of the overall immune response to environmentally encountered antigens and to relate this normal immunologic function to its occasional role in producing susceptibility to blood stream invasion by Gram negative bacteria. The model used will be disseminated disease due to Neisseria meningitidis. Increased levels of antigen specific serum IgA have been shown to induce susceptibility to disseminated meningococcal disease by blocking complement-mediated immune lysis, the primary effector mechanism restricting the organism to its commensal niche on the moist mucous membranes of man's upper respiratory tract. Such levels of antigen specific IgA are induced by enteric colonization by bacteria of diverse genera that elaborate surface antigens immunochemically indistinquishable from those of N. meningitidis. The molecular basis of IgA blockage will be sought by dissecting the interactions of surface antigens with Ig of the three majro isotypes, using ligand/receptor models, and their interactions with the alternative and classical complement pathways. The antigenic specificity of blocking IgA will be further identified, and the relationship of its induction to the epidemiology of meningococcal disease explored.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Immunological Sciences Study Section (IMS)
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University of California San Francisco
Schools of Medicine
San Francisco
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McLeod Griffiss, J; Brandt, B L; Saunders, N B et al. (2000) Structural relationships and sialylation among meningococcal L1, L8, and L3,7 lipooligosaccharide serotypes. J Biol Chem 275:9716-24
Hamadeh, R M; Galili, U; Zhou, P et al. (1995) Anti-alpha-galactosyl immunoglobulin A (IgA), IgG, and IgM in human secretions. Clin Diagn Lab Immunol 2:125-31
Jarvis, G A (1995) Recognition and control of neisserial infection by antibody and complement. Trends Microbiol 3:198-201
Hamadeh, R M; Estabrook, M M; Zhou, P et al. (1995) Anti-Gal binds to pili of Neisseria meningitidis: the immunoglobulin A isotype blocks complement-mediated killing. Infect Immun 63:4900-6
Jarvis, G A (1994) Analysis of C3 deposition and degradation on Neisseria meningitidis and Neisseria gonorrhoeae. Infect Immun 62:1755-60
Wetter, L A; Hamadeh, R M; Griffiss, J M et al. (1994) Differences in outer membrane characteristics between gallstone-associated bacteria and normal bacterial flora. Lancet 343:444-8
Hamadeh, R M; Jarvis, G A; Galili, U et al. (1992) Human natural anti-Gal IgG regulates alternative complement pathway activation on bacterial surfaces. J Clin Invest 89:1223-35
Jarvis, G A; Griffiss, J M (1991) Human IgA1 blockade of IgG-initiated lysis of Neisseria meningitidis is a function of antigen-binding fragment binding to the polysaccharide capsule. J Immunol 147:1962-7
Griffiss, J M; Yamasaki, R; Estabrook, M et al. (1991) Meningococcal molecular mimicry and the search for an ideal vaccine. Trans R Soc Trop Med Hyg 85 Suppl 1:32-6
Jarvis, G A; Griffiss, J M (1989) Human IgA1 initiates complement-mediated killing of Neisseria meningitidis. J Immunol 143:1703-9

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