Autoimmune diseases involve multiple genes. While functions of these genes are largely unknown, some may be related to an intrinsic hyperresponsiveness of B cells. B-cell responses are controlled by signaling thresholds through the B-cell antigen receptor (BCR) complex. The B1 isoform of type II IgG Fc receptors (FcgammaRIIB1) is exclusively expressed on B cells and serves as a negative regulator for inhibiting BCR-elicited activation. Thus, its allelic variants associated with functional deficits could be examined for possible associations with susceptibility to autoimmune diseases. We found that there are three types of polymorphisms in the reported FcgammaRIIB transcription regulatory regions in mouse strains. Compared to normal healthy mouse strains (group III), autoimmune disease-prone strains (group I) share three deletion sites: two in the promoter region and one in the third intron. Strains (group II) that per se are not autoimmune-prone, but have potentials to accelerate autoimmune diseases share two deletion sites in the third intron: one identical to that in group I and the other unique to group II. These polymorphisms correlated well with extents of down-regulation of FcgammaRIIB1 expression in germinal-center B cells upon stimulation with antigens and up-regulation of IgG antibody responses. Our data imply that these FcgammaRIIB polymorphisms are selected evolutionarily for natural defense against pathogens, and that such polymorphisms may, in turn, form the basis of one aspect of autoimmune susceptibility.

Serotonin [5-hydroxytryptamine (5-HT)] is a major therapeutic target of psychiatric disorders. Tryptophan hydroxylase (TPH) catalyzesthe rate-limiting reaction in the biosynthesis of 5-HT. Two isoforms (TPH1 and TPH2) having tryptophan hydroxylating activity were identified. Association studies have revealed possible TPH1 involvement in psychiatric conditions and behavioral traits. However, TPH1 mRNA was reported to be mainly expressed in the pineal gland and the periphery and to be barely detected in the brain. Therefore, contribution of TPH1 to brain 5-HT levels is not known, and the mechanisms how TPH1 possibly contributes to the pathogenesis of psychiatric disorders are not understood. Here, we show an unexpected role of TPH1 in the developing brain. We found that TPH1 is expressed preferentially during the late developmental stage in the mouse brain. TPH1 showed higher affinity to tryptophan and stronger enzyme activity than TPH2 in a condition reflecting that of the developing brainstem. Low 5-HT contents in the raphe nucleus were seen during development in New Zealand white (NZW) and SWR mice having common functional polymorphisms in the TPH1 gene. However, the 5-HT contents in these mice were not reduced in adulthood. In adult NZW and SWR mice, depression-related behavior was observed. Considering an involvement of developmental brain disturbance in psychiatric disorders, TPH1 may act specifically on development of 5-HT neurons, and thereby influence behavior later in life.

The diverse roles of monocytes in SLE and RA

The immune and nervous systems display considerable overlap in their molecular repertoire. Molecules originally shown to be critical for immune responses also serve neuronal functions that include normal brain development, neuronal differentiation, synaptic plasticity, and behavior. We show here that Fc␥RIIB, a low-affinity immunoglobulin G Fc receptor, and CD3 are involved in cerebellar functions. Although membranous CD3 and Fc␥RIIB are crucial regulators on different cells in the immune system, both CD3 and Fc␥RIIB are expressed on Purkinje cells in the cerebellum. Both CD3-deficient mice and Fc␥RIIB-deficient mice showed an impaired development of Purkinje neurons. In the adult, rotarod performance of these mutant mice was impaired at high speed. In the two knockout mice, enhanced paired-pulse facilitation of parallel fiberPurkinje cell synapses was shared. These results indicate that diverse immune molecules play critical roles in the functional establishment in the cerebellum.Some molecules originally shown to be critical for immune responses, such as the major histocompatibility complex (MHC) class I molecules, CD3, and semaphorin 7A (3,8,15,23), also serve neuronal functions. Based on studies of mutant mice, CD3 proved critical for the development of lateral geniculate nucleus (LGN) and long-term synaptic plasticity in the adult hippocampus (3,8).In the immune system, CD3 subunits are expressed on T cells. The T-cell receptor (TCR)-CD3 complex recognizing specific antigens bound to MHC present on antigen-presenting cells (APCs) is composed of a TCR heterodimer and CD3 polypeptides organized as dimers. The cell-cell interaction between APCs and T cells is known as an immunological synapse (5) in the mature immune system. In ␣␤ T cells, when the TCR interacts with the antigen/MHC complex, it transmits information to a signal-transducing complex consisting of two CD3 subunit dimers, CD3ε-CD3␥ and CD3ε-CD3␦, and the CD3-CD3 homodimer (10). Among CD3 subunits, CD3 is a crucial subunit having three immunoreceptor tyrosine-based activation motifs (ITAMs), whereas the remaining subunits have one ITAM (25). Tyrosine residues within these motifs are phosphorylated by src family tyrosine kinases, and then Src homology 2-containing proteins, including the tyrosine kinase ZAP70, participate in signaling (13). The signaling in ␥␦ TCRs is different from that in ␣␤ TCRs. Most ␥␦ TCRs lack CD3␦, and signal transduction by ␥␦ TCR is superior to that by ␣␤ TCR, as measured by its ability to induce calcium mobilization, extracellular signal-regulated kinase activation, and cellular proliferation (6).Fc␥RIIB is a low-affinity membrane receptor for immune complexes broadly distributed on hematopoietic cells, such as B cells, mast cells, basophils, macrophages, eosinophils, neutrophils, dendritic cells, and Langerhans cells. Fc␥RIIB negatively regulates B-cell receptor-induced signaling in B cells via the inhibitory immunoreceptor tyrosine-based inhibition motif in its cytoplasmic domain (24,30). Coengagement of the B-cell rece...

Objective. Fc␥ receptor type IIb (Fc␥RIIb) is a major negative regulator of B cells, and the lack of Fc␥RIIb expression has been reported to induce systemic lupus erythematosus (SLE) in mice of the C57BL/6 (B6) genetic background. The 129 strainderived Sle16 locus on the telomeric region of chromosome 1 including polymorphic Fcgr2b confers the predisposition to systemic autoimmunity when present on the B6 background. We undertook this study to examine the effect of the Sle16 locus on autoimmune disease in Fc␥RIIb-deficient B6 mice.Methods. We established 2 lines of Fc␥RIIb-deficient B6 congenic mouse strains (KO1 and KO2) by selective backcrossing of the originally constructed Fc␥RIIb-deficient mice on a hybrid (129 ؋ B6) background into a B6 background. Although both lack Fc␥RIIb expression, the KO1 and KO2 strains carry different lengths of the 129 strain-derived telomeric chromosome 1 segment flanked to the null-mutated Fcgr2b gene; the KO1 strain carries a 129 strainderived ϳ6.3-Mb interval distal from the null-mutated Fcgr2b gene within the Sle16 locus, while this interval in the KO2 strain is of B6 origin.Results. Unexpectedly, both strains failed to develop SLE; instead, the KO1 strain, but not the KO2 strain, spontaneously developed severe rheumatoid arthritis (RA) with an incidence reaching >90% at age 12 months.Conclusion. The current study shows evidence that the epistatic interaction between the Fcgr2b-null mutation and a polymorphic gene(s) in the 129 strainderived interval located in the distal Sle16 locus contributes to RA susceptibility in a new mouse model with the B6 genetic background, although the participation of other genetic polymorphisms cannot be totally excluded.