Mice homozygous for a disruption at the Lyn locus display abnormalities associated with the B lymphocyte lineage and in mast cell function. Despite reduced numbers of recirculating B lymphocytes, Lyn-/- mice are immunoglobulin M (IgM) hyperglobulinemic. Immune responses to T-independent and T-dependent antigens are affected. Lyn-/- mice fail to mediate an allergic response to IgE cross-linking, indicating that activation of LYN plays an indispensable role in Fc epsilon RI signaling. Lyn-/- mice have circulating autoreactive antibodies, and many show severe glomerulonephritis caused by the deposition of IgG immune complexes in the kidney, a pathology reminiscent of systemic lupus erythematosus. Collectively, these results implicate LYN as having an indispensable role in immunoglobulin-mediated signaling, particularly in establishing B cell tolerance.

Abstract. While the leukocyte integrin lymphocyte function-associated antigen (LFA)-I has been demonstrated to bind intercellular adhesion molecule (ICAM)-I, results with the related Mac-1 molecule have been controversial. We have used multiple cell binding assays, purified Mac-1 and ICAM-1, and cell lines transfected with Mac-1 and ICAM-1 cDNAs to examine the interaction of ICAM-1 with Mac-1. Stimulated human umbilical vein endothelial cells (HUVECs), which express a high surface density of ICAM-1, bind to immunoaffinity-purified Mac-1 adsorbed to artificial substrates in a manner that is inhibited by mAbs to Mac-1 and ICAM-1. Transfected murine L cells or monkey COS cells expressing human ICAM-1 bind to purified Mac-1 in a specific and dose-dependent manner; the attachment to Mac-1 is more temperature sensitive, lower in avidity, and blocked by a different series of ICAM-1 mAbs when compared to LFA-1. In a reciprocal assay, COS cells cotransfected with the o~ and/3 chain cDNAs of Mac-1 or LFA-1 attach to immunoaffinity-purified ICAM-1 substrates; this adhesion is blocked by mAbs to ICAM-1 and Mac-1 or LFA-1. Two color fluorescence cell conjugate experiments show that neutrophils stimulated with fMLP bind to HUVEC stimulated with lipopolysaccharide for 24 h in an ICAM-I-, Mac-l-, and LFA-l-dependent fashion. Because cellular and purified Mac-1 interact with cellular and purified ICAM-1, we conclude that ICAM-1 is a counter receptor for Mac-1 and that this receptor pair is responsible, in part, for the adhesion between stimulated neutrophils and stimulated endothelial cells.Primary event in the immune system's response to infectious agents is the recruitment of circulating neutrophils to the inflammatory site. Adhesion to the endothelium is the prerequisite physical step for extravasation to the peripheral site of injury. Neutrophil localization has been examined on a molecular level to define both the sequence of events that promotes neutrophil exit from the bloodstream and the cognate proteins on the surface of neutrophils and the endothelial cells that coordinate this interaction.The CDll/CDI8 family defines three high molecular weight, cell surface heterodimeric glycoproteins that have a broad distribution on leukocytes (53). This family, known as the leukocyte integrins, consists of lymphocyte functionassociated antigen (LFA)1-1 (CDlla/CD18; ot 175,000 Mr), Macq (CDllb/CD18; ct 160,000 Mr), and p150,95 (CDllc/ CD18; ot 150,000 Mr); the three proteins share a common 13 (CD18) chain (95,000 Mr) that is noncovalently associated with each unique a chain. These proteins are critical for adhesive functions in the immune system (29): mAbs to LFA-I block leukocyte adhesion to endothelial cells (16,56) 1. Abbt~oviations used in this paper: fMLR formyl methionine-leucinephenylalanine; HE, hydroethidine; HSA, human serum albumin; HUVEC, human umbilical vein endothelial cell; ICAM, intercellular adhesion molecule; IL, interleukin; LFA, lymphocyte function-associated antigen; SFDA, sulfofluorescein &acetate; TEA, trieth...

A B lymphocyte hyperactivity syndrome resembling systemic lupus erythematosus characterizes mice lacking the src-family kinase Lyn. Lyn is not required to initiate B cell antigen receptor (BCR) signaling but is an essential inhibitory component. lyn-/- B cells have a delayed but increased calcium flux and exaggerated negative selection responses in the presence of antigen and spontaneous hyperactivity in the absence of antigen. As in invertebrates, genetic effects of loci with only one functional allele can be used to analyze signaling networks in mice, demonstrating that negative regulation of the BCR is a complex quantitative trait in which Lyn, the coreceptor CD22, and the tyrosine phosphatase SHP-1 are each limiting elements. The biochemical basis of this complex trait involves a pathway requiring Lyn to phosphorylate CD22 and recruit SHP-1 to the CD22/BCR complex.