A human immune system (HIS) mouse model that dissociates roles for mouse and human FcR+ cells during antibody-mediated immune responses.

Human immune system (HIS) mice provide a model to study human immune responses in vivo. Currently available HIS mouse models may harbor mouse Fc Receptor (FcR)-expressing cells that exert potent effector functions following administration of human Ig. Previous studies showed that the ablation of the murine FcR gamma chain (FcR-γ) results in loss of antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis in vivo. We created a new FcR-γ-deficient HIS mouse model to compare host (mouse) versus graft (human) effects underlying antibody-mediated immune responses in vivo. FcR-γ-deficient HIS recipients lack expression and function of mouse activating FcRs and can be stably and robustly reconstituted with human immune cells. By screening blood B-cell depletion by rituximab Ig variants, we found that human FcγRs-mediated IgG1 effects, whereas mouse activating FcγRs were dominant in IgG4 effects. Complement played a role as an IgG1 variant (IgG1 K322A) lacking complement binding activity was largely ineffective. Finally, we provide evidence that FcγRIIIA on human NK cells could mediate complement-independent B-cell depletion by IgG1 K322A. We anticipate that our FcR-γ-deficient HIS model will help clarify mechanisms of action of exogenous administered human antibodies in vivo.

Defects in mucosal immunity and nasopharyngeal dysbiosis in HSC-transplanted SCID patients with IL2RG/JAK3 deficiency.

Both innate and adaptive lymphocytes have critical roles in mucosal defense that contain commensal microbial communities and protect against pathogen invasion. Here we characterize mucosal immunity in patients with severe combined immunodeficiency (SCID) receiving hematopoietic stem cell transplantation (HSCT) with or without myeloablation. We confirmed that pretransplant conditioning had an impact on innate (natural killer and innate lymphoid cells) and adaptive (B and T cells) lymphocyte reconstitution in these patients with SCID and now show that this further extends to generation of T helper 2 and type 2 cytotoxic T cells. Using an integrated approach to assess nasopharyngeal immunity, we identified a local mucosal defect in type 2 cytokines, mucus production, and a selective local immunoglobulin A (IgA) deficiency in HSCT-treated SCID patients with genetic defects in IL2RG/GC or JAK3. These patients have a reduction in IgA-coated nasopharyngeal bacteria and exhibit microbial dysbiosis with increased pathobiont carriage. Interestingly, intravenous immunoglobulin replacement therapy can partially normalize nasopharyngeal immunoglobulin profiles and restore microbial communities in GC/JAK3 patients. Together, our results suggest a potential nonredundant role for type 2 immunity and/or of local IgA antibody production in the maintenance of nasopharyngeal microbial homeostasis and mucosal barrier function.

Long-term therapeutic effects and safety of tacrolimus added to methotrexate in patients with rheumatoid arthritis.

To assess the long-term safety and efficacy of tacrolimus (TAC) used in combination with oral methotrexate (MTX) in patients with rheumatoid arthritis (RA) whose disease remains active despite treatment with MTX alone. The clinical courses of 24 RA patients who received TAC added to MTX from a single center were analyzed retrospectively. The disease activity was evaluated by the DAS28-ESR(3) every 12 months after the addition of TAC, and side effects were evaluated for 3 years. At 3 years after starting the treatment, TAC was still being used by 19 patients (79 %). The causes of discontinuation were an inadequate response (3 cases), oral ulcers and elevation of creatinine (1 case), and worsening of interstitial pneumonia (1 case). No death was registered. The DAS28-ESR(3) was decreased from 4.81 to 3.41 after 3 years of treatment. The doses of prednisolone were decreased from 5.1 mg/day to 3.2 mg/day after 3 years. In patients whose active RA persists despite treatment with MTX, TAC in combination with MTX is safe and well tolerated and provided clinical benefit for a long time in this single-center retrospective study. Further studies are required to confirm the safety and efficacy of this combination therapy.

Diagnosis and treatment of primary Sjögren syndrome-associated peripheral neuropathy: a six-case series.

OBJECTIVES: The clinical and therapeutic aspects of primary Sjögren syndrome (PSS) in patients with peripheral neuropathy were analyzed and the specifics of individual case studies are discussed. METHODS: We retrospectively studied six patients (four women, two men; mean age 64.5 years) presenting with PSS with peripheral neurological involvement over a five-year period (2008-2012). All patients had neurological examinations, including nerve conduction studies, somatosensory evoked potentials, and sural nerve biopsies. Treatment regimens included corticosteroids, intravenous gammaglobulin, or immunosuppressive treatment. RESULTS: Peripheral neuropathy was observed in six (7.9 %) of 76 patients with SS as the underlying disease; three were cases of multiple mononeuropathy, two cases had sensory ataxic neuropathy, one of which was autonomic neuropathy, and one case was diagnosed as painful sensory neuropathy without sensory ataxia. Four of the six patients were diagnosed with SS after the onset of neurological symptoms. Individual peripheral neuropathies had distinct neurological, electrophysiological, and pathological characteristics. The effect of steroids and intravenous gammaglobulin differed depending on the case. CONCLUSIONS: In PSS patients, a precise diagnosis is important, because the therapeutic strategy and response varies depending on the type of neuropathy. In clinical practice, it is important to consider a diagnosis of SS when patients present with peripheral neuropathy.

Intestinal microbiota link lymphopenia to murine autoimmunity via PD-1+CXCR5-/dim B-helper T cell induction.

T cell lymphopenia results in peripheral homeostatic expansion to maintain the T cell immune system, which is termed lymphopenia-induced proliferation (LIP). LIP is a potential risk for expanding autoreactive clones to become pathogenic in human and murine autoimmune diseases. However, the ontogeny of T cells that induce autoantibody production by autoreactive B cells in LIP remains unclear. Transfer of CD4+CD25- conventional T (Tc) cells into T-cell-deficient athymic nude mice has been previously reported as a LIP-induced autoimmune model which develops organ-specific autoimmune diseases and systemic antinuclear antibodies (ANAs). We show here that via LIP in this model, Tc cells proliferated and differentiated into PD-1+CXCR5-/dim B-helper T cells, which promoted splenic germinal center (GC) formation, provided help for autoantibody-producing B cells, and had distinctive features of follicular helper T (Tfh) cells except that they do not express high CXCR5. Intestinal microbiota were essential for their generation, since depletion of them in recipient mice by antibiotics resulted in a reduction of LIP-induced PD-1+CXCR5-/dim B-helper T cells and an amelioration of autoimmune responses. Our findings will contribute to the elucidation of the mechanism of lymphopenia-induced autoimmunity and autoantibody production, and will pave the way for microbiota-targeted novel therapeutic approaches to systemic autoimmune diseases.