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Two classes of IgG FcRs (FcγRI and FcγRIII) are stimulatory, whereas the third class (FcγRIIB) is inhibitory for immune cells. Although deficiency of the first two receptors protects against development of several autoimmune diseases, spontaneous systemic lupus erythematosus (SLE) develops in mice lacking the third receptor. To define the contribution of each receptor to SLE pathogenesis, Lin et al. (p. 1646 ) generated two derivative strains of the BXSB mouse that spontaneously develops SLE with autoantibody-induced immune complex (IC)-type glomerulonephritis. Both the strain with an intact stimulatory FcRγ chain plus a wild-type inhibitory FcγRIIB (BXSB.IIB^B6/B6) and the strain deficient in both the stimulatory FcRγ chain and inhibitory FcγRIIB (BXSB.γ^−/−) had increased survival, decreased thrombocytopenia and splenomegaly, fewer glomerular changes, and reduced renal failure compared with the BXSB parent strain. Only BXSB and BXSB.γ^−/− animals had total serum IgG and IgG anti-DNA Abs and glomerular IC deposition that increased with age. Phagocytosis of opsonized platelets correlated with degree of expression of stimulatory FcγRs on macrophages and was inhibited by FcγRIIB up-regulation. Immunofluorescent staining of spleen sections for T, B, and germinal center (GC) B cells demonstrated that white pulp in the two derivative strains was of normal size and architecture in contrast to that in the BXSB strain. GCs were prominent only in BXSB and BXSB.γ^−/− spleens but rare in BXSB.IIB^B6/B6 spleens; the GC B cells lacked FcγRIIB1 expression compared with BXSB.IIB^B6/B6 GCs. This use of congenic BXSB strains demonstrates that stimulatory FcγRs are involved in IC inflammation, whereas the inhibitory FcγR controls glomerular IC deposition in lupus-prone mice.

The innate and adaptive immune systems interact in pulmonary mucosa to protect the host against microbial infections while maintaining self-tolerance. Although innate immunity is known to influence allergic inflammation, the converse has not been explored. Beisswenger et al. (p. 1833 ) found increased viability of Pseudomonas aeruginosa washed from IL-4- plus IL-13-treated human airway epithelial cells grown in an air/liquid interface culture compared with P. aeruginosa washed from untreated cells. The cytokine-treated cells had reduced expression of human β-defensin-2 as measured by RT-PCR. Mice immunized and challenged with OVA before bacterial infection had greater influx of eosinophils, fewer neutrophils, lower concentrations of IL-1β and IL-6, and increased levels of IL-4 and IL-13 in their bronchoalveolar lavage fluid compared with infected nonsensitized animals. In addition, more viable bacteria were recovered from the lungs of the sensitized mice. The antimicrobial peptide CRAMP (cathelin-related antimicrobial peptide) was detected by immunoblotting in the bronchoalveolar lavage fluids from infected nonsensitized, but not sensitized, animals. The conclusion from these studies is that allergic airway inflammation inhibits the innate host defense of mucosal epithelium against infection by P. aeruginosa.

The soil-dwelling bacterium Tropheryma whipplei is the causative agent of Whipple’s disease, a rare multisystem disorder with predominant involvement of joints and the intestinal tract. Although the general immunocompetence of infected individuals is not compromised, Th1 reactivity in the periphery and in the intestinal mucosa is impaired. Moos et al. (p. 2015 ) undertook a study of T cell responses in 32 Whipple’s disease patients using lysates from T. whipplei cultured in fibroblasts. Controls were 16 healthy young subjects, 27 healthy age-matched subjects, 11 active triathletes (with enhanced exposure to environmental T. whipplei), and 17 patients with active tuberculosis. Only CD4⁺ T cells from patients with Whipple’s disease had significantly reduced IFN-γ production after exposure to T. whipplei lysates, and only Whipple’s disease patients had fewer bacteria-specific duodenal CD4⁺ T cells. No differences in reactivity to other microbial Ags were noted between Whipple’s disease patients and the three control groups with the exception that staphylococcal enterotoxin B stimulation resulted in a significantly higher percentage of IFN-γ-expressing CD69⁺ duodenal lymphocytes only among the patients’ cells. IL-2 stimulated IFN-γ production by T. whipplei-treated CD25⁺ T cells from healthy subjects but not those from Whipple’s disease patients who had higher percentages of activated duodenal and peripheral lymphocytes than controls. This study demonstrates a severe reduction in T. whipplei-specific Th1 cell responses in Whipple’s disease patients.

Experimental autoimmune oophoritis (EAO), a rat and mouse model of premature ovarian failure in humans, is characterized by initial increased fertility with elevated levels of follicle stimulating hormone (FSH), followed by loss of fertility. The ovarian Ag targeted by the autoantibodies has not been identified. Altuntas et al. (p. 1988 ) hypothesized that the disease might target the activins or inhibins produced in ovarian granulosa cells that regulate pituitary gonadotrophins. They found that CD4⁺ T cells from female mice immunized with an inhibin-α peptide, but not those from control animals, produced IFN-γ and IL-2 after in vitro stimulation with the peptide. CD3⁺ T cells were detected immunohistochemically in ovarian follicles 8 and 12 wk after peptide immunization. Immunized mice had longer estrous cycles (with shortened proestrus-estrus and lengthened metestrus-diestrus); 4 wk after immunization, they had increased numbers of ovarian follicles, increased serum concentrations of activin-A and FSH during estrus, and significantly increased serum levels of inhibin-α during estrus and metestrus. Females had larger litter sizes when mated 7–9 wk after immunization but significantly decreased fertility at 43–45 wk. Splenocytes activated with peptide in vitro, purified B cells, or sera, but not peptide-activated CD4⁺ T cells, from females immunized with peptide 4 wk earlier transferred EAO to naive recipients. IgG2b and IgG1 were the predominant serum anti-inhibin-α Ig isotypes. Sera from mice immunized 8 wk earlier with the inhibin peptide, but not control sera, prevented inhibin-mediated down-regulation of activin-induced FSH release from immortalized mouse pituitary cells in culture. Thus, the attack against the pituitary-gonadal regulatory axis in EAO is initiated by CD4⁺ T cells but mediated by anti-inhibin-α Abs that prevent down-regulation of FSH production in this biphasic mouse model of human premature ovarian failure.

Mouse thymus leukemia Ag (TL) is an MHC class lb molecule that binds with high affinity to CD8αα homodimers transiently expressed by activated T cells. CD8αα also is abundantly expressed by intraepithelial T lymphocytes (IELs) that reside close to TL-expressing epithelial cells in the small intestine. Pardigon et al. (p. 1590 ) speculated that TL interaction with CD8αα might represent a means of regulating the function and proliferation of IELs and in generating memory T cells. They detected acquisition of TL by IELs from TL⁻ C57BL/6 mice after incubation with mouse mastocytoma cells transfected with a TL-expressing plasmid. IELs activated by anti-CD3 mAb acquired more TL than nonactivated cells; TL transfer was blocked by an anti-CD8α mAb and did not occur in cells expressing a mutated CD8α chain or with TLs lacking the CD8α-binding region. Cotransfer of MHC class I molecules was not detected. Experiments using cells expressing a GFP-TL visualized by flow cytometry, real-time confocal microscopy, and cryo-immunoelectron microscopy indicated that transfer occurred during a single interaction, that the acquired molecule retained its original orientation in the membrane, and that transfer did not require formation of vesicles. Pretreatment with a PI3K inhibitor reduced the number of TL⁺ IELs by 50%. TL⁺ IELs bound more lectin than TL⁻ IELs, and IELs from mice with spontaneous chronic inflammatory bowel disease induced by treatment with a nonsteroidal anti-inflammatory drug had three times the amount of bound TL compared with IELs from normal controls. The authors speculate that TL “snatched” from epithelial cells may alter IEL functional interactions with other cells in the small intestine.

Tumors can evade the immune system by immunoediting, i.e., altering their phenotype by loss of Ag or immune recognition molecules. Disis and colleagues reported that spontaneous breast tumors in neu-transgenic (neu-tg) mice rapidly developed Ag-negative variants after anti-neu mAb-treatment; transplanted breast tumors in the parental mice lacking a transgene (neu⁻) also lost neu Ag. However, it is not known how immunoediting occurs. In a continuation of their studies, Knutson et al. (p. 1526 ) injected the neu-tg and neu⁻ mice with cells from a spontaneously arising neu-tg mouse mammary carcinoma (MMC). Tumors that grew in neu⁻ recipients developed with a prolonged latent period compared with those in neu-tg recipients. Cell lines established from the tumors had low neu expression as measured by flow cytometry, mRNA gels, and immunoblotting but retained the neu gene and expressed normal levels of MHC class I Ag. The Ag-negative tumor cells rapidly induced tumors in neu-tg or neu⁻ mice. Animals depleted of CD4⁺ T cells were unable to reject the neu⁺ MMC cells. Ag-negative tumor cell junctions were less tight, and the cells were more spindle-shaped than the epithelial MMC cells. An RNA microarray and RT-PCR showed that Ag-negative tumor cells expressed mesenchymal genes, but MMC cells expressed epithelial genes. Flow cytometry indicated that down-regulation of CD24 expression accompanied transition of MMC cells to Ag negativity. Ag-negative cells expressed five matrix metalloproteinases and three tumor invasion-associated proteins not detected in MMC cells and were more invasive in in vitro migration assays. The authors demonstrate that immunoediting of these breast tumor cells involves an epithelial to mesenchymal transition with loss of Ag expression, altered morphology, and up-regulated expression of invasion-related proteins.

Bachmann and colleagues screened a cDNA library prepared from a patient with systemic lupus erythematosus with the patient’s serum and detected expression of a premature termination mutant of nuclear protein La/SS-B. It is not understood how the mutated mRNA was able to escape degradation by nonsense-mediated decay of mRNA (RNA surveillance) aimed at protecting the cell against deleterious effects of truncated mutant proteins. In additional experiments, Bachmann et al. (p. 1698 ) showed that ∼30% of sera from anti-La positive autoimmune patients recognized the truncated protein on immunoblots and in ELISA. Mice transgenic for cDNA encoding the N-domain of mutant human La expressed transgene mRNA and protein in all tissues analyzed. Mutant La protein was found in the cytoplasm by immunostaining, whereas native La transgene in control mice was localized in the nucleus. In addition to the truncated La protein, full-length human La protein was detected on immunoblots of tissue extracts from mice transgenic for mutant La using a mAb specific for the human La C-domain. Presumably, ribosomal frame shifting generated the full-length protein. Proteinuria, immune complex nephritis, and anti-La autoantibodies developed in mice transgenic for mutant La but not in animals transgenic for normal La. The escape of mutant La mRNA from RNA surveillance allows expression of the truncated form of La that results in a lupus phenotype in mice transgenic for the mutated human protein.

Summaries written by Dorothy L. Buchhagen, Ph.D.