Founders 

      Jeffrey V. Ravetch

Genetics of the adaptive immune response

The Laboratory of Molecular Genetics and Immunology is focussed on dissecting the cellular and molecular mechanisms governing the generation of antibody specificity and the translation of that specificity into cellular responses. Our work seeks to identify the genetic components which initiate B cell activation upon antigenic challenge, the controls which maintain tolerance both centrally and in the periphery and the mechanisms which govern the coupling of antibody specificity to effector cell response. Our entry point into this system has been through the analysis of systemic autoimmunity in murine models of disease through the investigation of the genesis and fate of the pathological antigen-antibody complexes which form in these diseases and trigger tissue damage. This complex problem has been simplified by focussing on the mechanisms by which immune complexes influence both the afferent and efferent immune responses through their interaction with a family of low-affinity surface receptors, the Fc receptors. These receptors are expressed as pairs of activation and inhibitory molecules, providing a mechanism for establishing thresholds for cellular triggering and for terminating the activation response. Each function is critical for maintaining tolerance and modulating effector cell activation. Perturbations of these pathways have revealed the central role these receptors play in appropriate immune responses.

Recent Publications

Sylvestre D, Clynes R, Ma MG, Warren H, Carroll MC, Ravetch JV. Immunoglobulin G-mediated inflammatory responses develop normally in complement-deficient mice. J EXP MED 1996 DEC;184(6):2385-2392

Seykora JT, Aderem A, Myat MM, Allen LAH, Ravetch JV. Molecular determinants of the myristoyl-electrostatic switch of MARCKS J. Biol. Chem. 1996;271(31):18797-18802

Ono M, Okada H, Bolland S, Yanagi S, Kurosaki T, Ravetch JV. Deletion of SHIP or SHP-1 reveals two distinct pathways for inhibitory signaling. CELL 1997 JUL;90(2):293-301

Vora KA, Ravetch JV, Manser T. Amplified follicular immune complex deposition in mice lacking the Fc receptor gamma-chain does not alter maturation of the B cell response. J IMMUNOL 1997 SEP;159(5):2116-2124

Ravetch JV. Fc receptors. CURR OPIN IMMUNOL 1997 FEB;9(1):121-125

Miyajima I, Dombrowicz D, Martin TR, Ravetch JV, Kinet JP, Galli SJ. Systemic anaphylaxis in the mouse can be mediated largely through IgG, and Fc gamma RIII - Assessment of the cardiopulmonary changes, mast cell degranulation, and death associated with active or IgE- or IgG(1)-dependent passive anaphylaxis. J CLIN INVEST 1997 MAR;99(5):901-914

Dombrowicz D, Flamand V, Miyajima I, Ravetch JV, Galli SJ, Kinet JP. Absence of Fc(epsilon)RI alpha chain results in upregulation of Fc gamma RIII-dependent mast cell degranulation and anaphylaxis - Evidence of competition between Fc(epsilon)RI and Fc gamma RIII for limiting amounts of FcR beta and gamma chains. J CLIN INVEST 1997 MAR;99(5):915-925

Clynes R, Takechi Y, Moroi Y, Houghton A, Ravetch JV. Fc receptors are required in passive and active immunity to melanoma. PROC NAT ACAD SCI USA 1998 JAN;95(2):652-656

Suzuki Y, Shirato I, Okumura K, Ravetch JV, Takai T, Tomino Y, Ra CS. Distinct contribution of Fc receptors and angiotensin II- dependent pathways in anti-GBM glomerulonephritis. KIDNEY INT 1998 OCT;54(4):1166-1174

Bolland S, Pearse RN, Kurosaki T, Ravetch JV. SHIP modulates immune receptor responses by regulating membrane association of Btk. IMMUNITY 1998 APR;8(4):509-516

Shores EW, Ono M, Kawabe T, Sommers CL, Tran T, Lui K, Udey MC, Ravetch J, Love PE. T cell development in mice lacking all T cell receptor zeta family members (zeta, eta, and Fc epsilon RI gamma). J EXP MED 1998 APR;187(7):1093-1101

Ravetch JV, Clynes RA. Divergent roles for Fc receptors and complement in vivo. ANNU REV IMMUNOL 1998;16():421-432

Yuan RR, Clynes R, Oh J, Ravetch JV, Scharff MD. Antibody-mediated modulation of Cryptococcus neoformans infections is dependent on distinct Fc receptor functions and IgG subclasses. J EXP MED 1998 FEB;187(4):641-648

Wu J, Qin D, Ravetch J, Szakal AK, Tew JG. Role of follicular dendritic cells (FDC) in rendering immune complexes highly immunogenic. J LEUKOCYTE BIOL 1998;():34

Clynes R, Dumitru C, Ravetch JV. Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis. SCIENCE 1998 FEB;279(5353):1052-1054

Okada H, Bolland S, Hashimoto A, Kurosaki M, Kabuyama Y, Iino M, Ravetch JV, Kurosaki T. Cutting edge: Role of the inositol phosphatase SHIP in B cell receptor-induced Ca2+ oscillatory response. J IMMUNOL 1998 NOV;161(10):5129-5132

Jankovic D, Cheever AW, Kullberg MC, Wynn TA, Yap G, Caspar P, Lewis FA, Clynes R, Ravetch JV, Sher A. CD4+ T cell-mediated granulomatous pathology in schistosomiasis is downregulated by a B cell-dependent mechanism requiring Fc receptor signaling. J EXP MED 1998 FEB;187(4):619-629

Clynes R, Maizes JS, Guinamard R, Ono M, Takai T, Ravetch JV. Modulation of immune complex-induced inflammation in vivo by the coordinate expression of activation and inhibitory Fc receptors. J EXP MED 1999 JAN;189(1):179-185

Yuasa T, Kubo S, Yoshino T, Ujike A, Matsumura K, Ono M, Ravetch JV, Takai T. Deletion of Fc gamma receptor IIB renders H-2(b) mice susceptible to collagen-induced arthritis. J EXP MED 1999 JAN;189(1):187-194

Guinamard R, Signoret N, Masamichi I, Marsh M, Kurosaki T, Ravetch JV. B cell antigen receptor engagement inhibits stromal cell-derived factor (SDF)-1 alpha chemotaxis and promotes protein kinase C (PKC)-induced internalization of CXCR4. J EXP MED 1999 MAY 3;189(9):1461-1466

Ujike A, Ishikawa Y, Ono M, Yuasa T, Yoshino T, Fukumoto M, Ravetch JV, Takai T. Modulation of immunoglobulin (Ig)E-mediated systemic anaphylaxis by low-affinity Fc receptors for IgG. J EXP MED 1999 MAY 17;189(10):1573-1579

Pearse RN, Kawabe T, Bolland S, Guinamard R, Kurosaki T, Ravetch JV. SHIP recruitment attenuates Fc gamma RIIB-induced B cell apoptosis. IMMUNITY 1999 JUN;10(6):753-760

Fossati-Jimack L, Reininger L, Chicheportiche Y, Clynes R, Ravetch JV, Honjo T, Izui S. High pathogenic potential of low-affinity autoantibodies in experimental autoimmune hemolytic anemia. J EXP MED 1999 DEC 6;190(11):1689-1696

Kubagawa H, Chen CC, Ho LH, Shimada T, Gartland L, Mashburn C, Uehara T, Ravetch JV, Cooper MD. Biochemical nature and cellular distribution of the paired immunoglobulin-like receptors, PIR-A and PIR-B. J EXP MED 1999 JAN;189(2):309-317

Qin DH, Wu JH, Vora KA, Ravetch JV, Szakal AK, Manser T, Tew JG. Fc gamma receptor IIB on follicular dendritic cells regulates the B cell recall response. J IMMUNOL 2000 JUN 15;164(12):6268-6275

Guinamard R, Okigaki M, Schlessinger J, Ravetch JV. Absence of marginal zone B cells in Pyk-2-deficient mice defines their role in the humoral response. NAT IMMUNOL 2000 JUL;1(1):31-36

Ravetch JV, Lanier LL. Immune inhibitory receptors. SCIENCE 2000 OCT 6;290(5489):84-89

Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. NATURE MED 2000 APR;6(4):443-446

Bolland S, Ravetch JV. Spontaneous autoimmune disease in Fc gamma RIIB-deficient mice results from strain-specific epistasis. IMMUNITY 2000 AUG;13(2):277-285

Takai T, Nakamura A, Yuasa T, Ujike A, Ono M, Nukiwa T, Ravetch JV. Fc gamma receptor IIB-deficient mice develop Goodpasture's Syndrome upon immunization with type IV collagen. FASEB J 2000 APR 20;14(6):A994

Nakamura A, Yuasa T, Ujike A, Ono M, Nukiwa T, Ravetch JV, Takai T. Fc gamma receptor IIB-deficient mice develop Goodpasture's syndrome upon immunization with type IV collagen: A novel murine model for autoimmune glomerular basement membrane disease. J EXP MED 2000 MAR 6;191(5):899-905

Ravetch JV, Bolland S. IgG Fc receptors. ANNU REV IMMUNOL 2001;19():275-290

Samuelsson A, Towers TL, Ravetch JV. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. SCIENCE 2001 JAN 19;291(5503):484-486

Khalil M, Inaba K, Steinman R, Ravetch J, Diamond B. T cell studies in a peptide-induced model of systemic lupus erythematosus. J IMMUNOL 2001 FEB 1;166(3):1667-1674