B Cell-activating factor (BAFF): A promising trans-nosographic biomarker of inflammation and autoimmunity in bipolar disorder and schizophrenia.

Immune dysregulation is an important aspect of schizophrenia (SZ) and bipolar disorders (BD) pathophysiology, including not only inflammatory but also autoimmune process reflective of abnormal humoral immune responses. Given that B cell-activating factor (BAFF) is an integral aspect of B lymphocyte regulation, the current study investigated BAFF in SZ and BD. 255 SZ patients, 407 BD patients and 185 healthy controls (HC) were investigated across three aspects of soluble BAFF (sBAFF) by (i) comparing sBAFF circulatory levels across SZ, BD and HC, (ii) determining potential correlations between the circulating levels of sBAFF and the genotype distribution of a functionally relevant polymorphism, namely the TNFSF13B 3'UTR insertion-deletion polymorphism (GCTGT>A), (iii) analyzing relationships between both sBAFF levels and 3'UTR insertion-deletion genotypes and disease risk, patients clinical characteristics and circulating levels of potent inflammatory molecules. In addition, in subsets of patients, we also searched for possible correlations between sBAFF levels and stigma of past infectious events as well as positivity for circulating systemic autoantibodies or those directed against central nervous system (CNS) structures. Studying blood derived serum and DNA, weobserved that circulating sBAFF levels were significantly higher in SZ and BD patients, versus HC (p = 5.3*10-10and p = 4.4*10-09). Patients experiencing acute episodes, versus stable patients, in between acute episodes, exhibited higher sBAFF levels (p = 0.017).In SZ patients, positive correlations were observed between elevated sBAFF levels and: (i) elevated positive psychotic symptoms (PANSS pos), (ii) history of childhood trauma (physical abuse), and (iii) low scores on global functioning (GAF) (p = 0.024, p = 0.024, and p = 0.041).We also found that the distribution of the BAFF Ins/Del genotypes was significantly correlated with circulating sBAFF levels in SZ and BD patients (p = 0.0004). Elevated sBAFF levels were also correlated with increased levels of pro-inflammatory markers in both SZ and BD cohorts (p < 0.001). Regarding infectious stigma, only patients seropositive, versus seronegative, for herpes simplex virus (HSV)1 immunoglobulin (Ig)G antibodies exhibited a significant association with high sBAFF levels (p = 0.013). In contrast, positivity for systemic or CNS autoantibodies was significantly associated with reduced sBAFF levels, compared to patients without autoantibodies (p = 0.0017). Overall, our findings indicate that BAFF may be a promising trans-nosographic biomarker of inflammation that is likely to offer predictive, diagnostic, and prognostic tools for the management of SZ and BD. The results therefore have practicable clinical utility given the availability of immunotherapeutic treatment options including targeted monoclonal antibodies against BAFF.

Paraneoplastic pemphigus uncovers distinct clinical and biological phenotypes of western unicentric Castleman disease.

Unicentric Castleman disease (UCD) is a lymphoproliferative disease of unknown cause. Paraneoplastic pemphigus (PNP) is a major complication shown to be associated with a poor prognosis, with particular severity in patients with bronchiolitis obliterans (BO). This study describes the clinical and biological characteristics of UCD-PNP patients in a large Western cohort. A total of 148 patients diagnosed with UCD were identified, including 14 patients with a defined PNP. PNP was significantly associated with myasthenia gravis (MG) and FDC sarcoma during follow-up (FDCS). PNP was also significantly associated with reduced survival. These data, together with a multivariate analysis by principal components, led to the identification of UCD-PNP as a group at risk of MG, FDCS and death. PDGFRB sequencing performed on UCD lesions from six patients found the gain-of-function p.N666S variant in two. Interestingly, both patients had hyaline-vascular UCD subtype, were in the UCD-PNP subgroup and had FDCS. Sera from 25 UCD-PNP patients and 6 PNP patients without UCD were tested for PNP-associated autoantibodies. Sera from UCD-PNP patients had a strong reactivity against the N-terminal domain of recombinant periplakin (rPPL, 82%) and showed reactivity against at least two domains of rPPL. These features were not found in patients with UCD alone or in the PNP group without UCD. These data indicate that UCD-PNP patients belong to a subgroup sharing strong clinical and biological identity that might help to decipher the different dynamics of UCD natural history.

Dermatopulmonary Syndrome Associated With Anti-MDA5 Antibodies After Allogeneic Hematopoietic Stem Cell Transplantation.

IMPORTANCE: Chronic graft-vs-host-disease (cGVHD) after allogeneic stem cell transplantation (AHSCT) may resemble autoimmune diseases. Anti-MDA5 (melanoma differentiation-associated gene 5) dermatopulmonary syndrome is a subset of dermatomyositis defined by specific clinical features and detection of anti-MDA5-antibodies in the serum. OBJECTIVE: To characterize the clinical features of patients who underwent AHSCT and screened positively for anti-MDA5 antibodies. DESIGN, SETTING, AND PARTICIPANTS: For this monocentric retrospective study, we exained 81 patients screened for anti-MDA5 antibodies at a specific dermatological or pulmonary postallograft consultation between January 2014 to September 2015 at a National Reference Center; 2 additional patients not seen at this consultation but having clinical features suggestive of anti-MDA5 syndrome were included. Twenty serum samples from patients after AHSCT without cGVHD were used as controls. MAIN OUTCOMES AND MEASURES: Anti-MDA5 antibodies screened using an immunodot assay. RESULTS: Of 83 patients who underwent AHSCT (mean [SD] age, 47 [14] years), 6 patients tested positive for anti-MDA5 antibodies (mean [SD] age, 43 [16] years) including 4 patients with interstitial lung disease and 3 patients with cutaneous clinical features similar to anti-MDA5 skin symptoms encountered in patients who have not undergone AHSCT, namely finger pad inflammation, palmar violaceous papules, and digital ulcerations. Three patients had severe respiratory symptoms resistant to systemic steroids, and 1 patient died of severe interstitial lung disease. CONCLUSIONS AND RELEVANCE: The clinical features and long-term prognosis of patients who underwent AHSCT and test positively for anti-MDA5 antibodies should be evaluated in large prospective studies.

CD24(hi)CD27⁺ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease.

Interleukin 10 (IL-10)-producing B cells (regulatory B cells [Bregs]) regulate autoimmunity in mice and humans, and a regulatory role of IL-10-producing plasma cells has been described in mice. Dysfunction of B cells that maintain homeostasis may play a role in the pathogenesis of chronic graft-versus-host disease (cGVHD) after allogeneic stem cell transplantation. Here, we found a relation between decreased Breg frequencies and cGVHD severity. An impaired ability of B cells to produce IL-10, possibly linked to poor signal transducer and activator of transcription 3 and extracellular signal-regulated kinase phosphorylation, was found in patients with active cGVHD. IL-10 production was not confined to a single B-cell subset, but enriched in both the CD24(hi)CD27(+) and CD27(hi)CD38(hi) plasmablast B-cell compartments. In vitro plasmablast differentiation increased the frequency of IL-10-producing B cells. We confirmed that allogeneic transplant recipients had an impaired reconstitution of the memory B-cell pool. cGVHD patients had less CD24(hi)CD27(+) B cells and IL-10-producing CD24(hi)CD27(+) B cells. Patients with cGVHD had increased plasmablast frequencies but decreased IL-10-producing plasmablasts. These results suggest a role of CD24(hi)CD27(+) B-cell and plasmablast-derived IL-10 in the regulation of human cGVHD.

Anti-Angiotensin type 1 receptor antibodies in chronic graft-versus-host disease.

BACKGROUND: Activating anti-angiotensin type 1 receptor antibodies (AT1R-AA) have been described in patients with systemic scleroderma, an auto-immune disorder with clinical fibrotic features. Chronic graft-versus-host disease (cGvHD) after hematopoietic stem cell transplantation may have clinical fibrotic features, whose pathogenesis may be similar with systemic sclerosis. OBJECTIVE: To evaluate the presence of AT1R-AA and their association with clinical and biological symptoms in cGvHD patients. MATERIAL AND METHODS: Sera from 87 patients including 45 extensive cGvHD and 42 hematopoietic stem cell transplantation patients without cGvHD were retrospectively analyzed for the presence of AT1R-AA using an enzymatic immunoassay. RESULTS: The frequency of AT1R-AA was significantly increased (odds ratio [OR]=3.4, P=0.04) in the cGvHD group (24.4%) compared with the non-cGvHD group (7.1%). In the cGvHD group the positivity of AT1R-AA was significantly associated with: i/ the presence of antinuclear antibodies (OR=5.9, P=0.04) ii/ a more severe global and organ-specific cGvHD scoring (P<0.05), iii/ the presence of active skin or mucosal erosions (OR=19.2, P<0.01). There was no difference between the number and the types of organs involved by the cGvHD between the AT1R-AA-positive versus AT1R-AA-negative subgroups. CONCLUSION: This preliminary study suggests a potential role and prognostic value of AT1R-AA in cGvHD.

Performance evaluation of three assays for the detection of PR3-ANCA in granulomatosis with polyangiitis in daily practice.

BACKGROUND: Anti-neutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3-ANCA) are a serological hallmark of small vessel vasculitis, particularly granulomatosis with polyangiitis (GPA). To increase their sensitivity, some ELISA employ the human native PR3 combined with a recombinant protein. Their specificity in daily practice is still to be defined. Our objective was to compare the performance for GPA diagnosis of three PR3-ANCA assays in daily practice. PATIENTS AND METHODS: Seventy-eight consecutive patients' sera with suggestive IIF were included. All sera were tested with a routine Enzyme Linked Immuno adsorbant Assay (ELISA) employing a mixture of human native and human recombinant (hn+hr) PR3 (EUROIMMUN™) compared to two assays using immobilized purified human PR3 (QUANTA Lite(®) ELISA and QUANTA Flash(®) Chemiluminescence assay (CIA), INOVA Diagnostics). Clinical data including BVAS score were collected retrospectively. RESULTS: Nineteen out of the 78 patients had GPA. The hn+hr PR3 ELISA had a good sensitivity (100%) but a lower specificity for the diagnosis of GPA (61.0%) than the assays using the sole native protein (hn ELISA: 81.4%, hn CIA: 69.5%). False positive results mainly consisted of patients with inflammatory bowel disease, who had a specific PR3-ANCA positivity assembly when coupling the assays. The antibody titers by human native PR3 assays, but not hn+hr assay, positively correlated with BVAS score. CONCLUSION: These results highlight the need of a close collaboration between physicians and immunologists. Combining assays including last generation CIA employing human native antigens should improve the performance of GPA's diagnosis.

Increased angiogenesis and enhanced bone formation in patients with IgM monoclonal gammopathy and urticarial skin rash: new insight into the biology of Schnitzler syndrome.

Schnitzler syndrome is a rare plasma cell disorder the pathogenesis of which is still not fully understood. We evaluated the circulating levels of four major angiogenic cytokines (VEGF, angiogenin, angiopoietin-1 and angiopoietin-2) and six bone remodeling markers (sRANKL, osteoprotegerin, dickkopf-1, CTX, osteocalcin and bone-specific alkaline phosphatase-bALP) in 13 patients with Schnitzler syndrome. At diagnosis, patients had elevated angiogenic cytokines. The mean VEGF levels were almost 3.5-fold higher in Schnitzler syndrome compared to controls, while 10 of 13 patients had higher VEGF than the upper control value. Successful treatment led to a significant reduction in VEGF. Patients with Schnitzler syndrome had increased bone formation (high bALP, osteocalcin and osteoprotegerin) which was not balanced by an increase in bone resorption (normal CTX and sRANKL). These data support a role for VEGF as a new minor criterion in the diagnosis and follow up of Schnitzler syndrome, while the uncoupling of bone remodeling in favor of bone formation justifies the presence of bone densification.

The spectrum of lung involvement in collagen vascular-like diseases following allogeneic hematopoietic stem cell transplantation: report of 6 cases and review of the literature.

Multisystem autoimmune diseases occurring after allogeneic hematopoietic stem cell transplantation are infrequent, late-onset manifestations that resemble well-defined collagen vascular disorders. Because the lung is frequently involved in the course of connective tissue disorders, we focused on lung manifestations occurring in autoimmune diseases following allogeneic stem cell transplantation. In the present series, we report 6 patients with systemic lupus erythematous, mixed connective tissue disease, Sjögren syndrome, polymyositis, and ANCA-positive vasculitis who presented with a spectrum of pulmonary manifestations affecting the airways, lung parenchyma, and probably respiratory muscles. We identified 3 different histopathologic patterns of interstitial pneumonia consistent with the underlying autoimmune disorder: lymphocytic interstitial pneumonia and non-specific interstitial pneumonia in 2 patients with Sjögren syndrome and diffuse alveolar damage in 1 patient with ANCA-positive vasculitis. These lung manifestations had poor prognoses. Further studies are needed to determine the optimal therapy for these complications.

MICA-129 genotype, soluble MICA, and anti-MICA antibodies as biomarkers of chronic graft-versus-host disease.

The MHC class I-related chain A (MICA) molecules exist as membrane-bound and soluble isoforms and are encoded by a polymorphic gene. Their genetic and phenotype characteristics have been studied in various pathologic settings but not in the context of hematopoietic stem cell transplantation (HSCT). Here, we evaluated whether MICA-related features namely MICA-129 gene polymorphism, serum levels of soluble MICA (sMICA) and anti-MICA antibodies (MICA Abs) before and after HSCT could influence the incidence of chronic graft-versus-host disease (cGVHD) and relapse of their disease in 211 HLA-identical sibling pairs and in a subset of 116 recipients, respectively. Although the MICA-129 val/val genotype and elevated sMICA serum levels after HSCT are independently associated with the incidence of cGVHD (P = .002 and .001) regardless of history of acute GVHD, the presence of MICA Abs before transplantation confers protection against cGVHD (P = .04). There is an inverse relationship between MICA Abs and sMICA, suggesting an antibody-based neutralization of deleterious effects of sMICA. Similarly, these genetic and phenotype characteristics of MICA influence the incidence of relapse. Altogether, these data suggest that the studied MICA genotype and phenotype specificities could be used as relevant biomarkers for cGVHD monitoring.

Frequent antibody production against RARalpha in both APL mice and patients.

In an acute promyelocytic leukemia (APL)-transplantable mouse model, we previously reported the presence of antibodies recognizing PML-RARalpha and RARalpha in the sera of ATRA-treated mice. To evaluate this immune response, we determined the prevalence of anti-RARalpha antibodies in a cohort of 48 APL mice, treated by ATRA (n = 24) or by placebo pellets (n = 24), and in a preliminary subset of 9 patients with APL using a specific enzyme-linked immunosorbent assay (ELISA). In APL mice, significantly higher antibody levels were observed at the latest time points (day 48 to 58 levels superior to day 15 to 18 or day 28 to 38 levels). Antibody levels were higher in ATRA-treated mice than in placebo-treated mice and were also predictive of better survival. In the patients with APL, anti-RARalpha antibodies were detected at diagnosis and after maintenance therapy, reminiscent of the ATRA-treated APL mice. Antinuclear or antineutrophil cytoplasmic autoantibodies were also detected. These data reveal for the first time that in patients with APL an immune response may be detected at diagnosis and enhanced after maintenance therapy.

Analysis of immune reconstitution after autologous bone marrow transplantation in systemic sclerosis.

OBJECTIVE: To analyze hematopoietic and immune reconstitution after autologous hematopoietic stem cell transplantation (HSCT) in 7 patients with systemic sclerosis (SSc). METHODS: Two groups of patients were retrospectively constituted according to whether they had a favorable clinical response (group A; n = 4) or no response or a relapse of disease (group B; n = 3) after HSCT. Immune reconstitution was analyzed every 3 months using lymphocyte immunophenotyping, alpha/beta T cell receptor (TCR) diversity analysis, and ex vivo thymic function analysis by quantification of TCR rearrangement excision circles (TRECs). RESULTS: Patients had similar characteristics at study entry, except for a lower modified Rodnan skin thickness score (P = 0.03) and a lower Health Assessment Questionnaire score (P = 0.05) in group A than in group B. The number of reinjected cells and the time to hematopoietic reconstitution were similar in both groups. The absolute numbers of CD19+ and CD20+ B cells were lower in group A than in normal controls (P < 0.05) and within the normal range in group B. Absolute numbers of T and natural killer lymphocytes were normal before HSCT. Numbers of CD3+ cells remained low thereafter. Numbers of CD8+ cells were back to normal 3 months after HSCT in both groups. B cell counts were low until 6 months after HSCT in group A and stayed in the normal range in group B. The CD3+ defect was sustained in group A, with an opposite trend and a faster CD4+ reconstitution profile in group B. The T cell repertoire was skewed before and until 1 year after HSCT, with shared expansions before and after transplant in a given individual. TREC values correlated negatively with C-reactive protein levels (r(s) = -0.41, P = 0.001) and positively with CD19+ (r(s) = 0.35, P = 0.001) and CD20+ (r(s) = 0.34, P = 0.002) lymphocyte counts. CONCLUSION: B and T lymphocyte populations remained disturbed for at least 1 year after HSCT in SSc patients, which may reflect the persistence of an underlying disease mechanism.

Antineutrophil cytoplasmic antibody-associated neutropenia.

BACKGROUND: Antineutrophil cytoplasmic antibodies (ANCA) can be associated with various disorders. However, their association with neutropenia has never been reported. METHODS: Nine patients with chronic unexplained neutropenia and ANCA were studied. Clinical charts were extensively analyzed and all patients underwent hematological and immunological investigations. RESULTS: All patients (6 women and 3 men) were Caucasian and had a mean age of 49 years (range 16-67 years). All presented with a neutropenia below 1.5x10(9)/L for more than 6 months. The neutropenia was <0.5x10(9)/L in six cases and moderate in three. There was no evidence of toxic- or drug-related neutropenia or of a hematological malignancy. Autoimmune anemia and/or thrombocytopenia were present in five patients. ANCA, with various specificities, were present in all patients. ANCA were associated with various other autoantibodies in eight patients, including antisurface-neutrophil antibodies in three cases. Four of the six patients with severe neutropenia experienced infections. Five patients were treated with hematopoietic growth factors, steroids, intravenous immunoglobulins, splenectomy, methotrexate and/or cyclophosphamide, allowing the neutrophil count to be restored transiently or permanently. CONCLUSIONS: A subset of patients with neutropenia of possible autoimmune origin may develop ANCA. Their detection would provide strong evidence of an autoimmune mechanism. Neutropenia should be added to the list of ANCA-associated diseases.

Autoimmune cytopenias associated with autoantibodies to nuclear envelope polypeptides.

A subset of anti-nuclear autoantibodies (ANA) are directed against nuclear envelope (NE) polypeptides and display by indirect immunofluorescence (IIF) a ring-like fluorescent pattern. We report herein 19 patients with autoimmune cytopenias associated with antibodies (Abs) to NE polypeptides. Anti-NE specificity was determined by immunoblot, using NE preparations and purified lamina fractions. Eleven sera reacted with lamin B(1), and two reacted with both lamin B(1) and an unidentified 150-kDa protein (p150). One serum reacted with only p150. Four sera reacted with lamins A and C, and one reacted with and an unidentified 52-kDa NE polypeptide (p52). Autoimmune cytopenias included hemolytic anemia (7 cases), thrombocytopenia (13 cases), and neutropenia (6 cases). Five patients had 2 (3 cases) or 3 (2 cases) different cytopenias. Antiphospholipid antibodies (APLA) were detected in 14 patients, 2 of whom experienced thromboembolic events. A liver disorder was present in 7 patients. Systemic lupus erythematosus and lupus-like syndrome were diagnosed in 11 and 2 patients, respectively. Cytopenias responded to steroids alone (13 patients), or together with intravenous immunoglobulins (2 patients), or cyclophosphamide (2 patients). Two patients did not require treatment. Our results suggest that anti-NE Abs need to be sought for in patients with peripheral cytopenias, particularly when they are associated with APLA and/or liver disorders. Their detection strongly suggests an autoimmune process. Such cytopenias are often manifestations of a lupus or lupus-like disease and are responsive to steroids.

Severe ADAMTS13 deficiency in adult idiopathic thrombotic microangiopathies defines a subset of patients characterized by various autoimmune manifestations, lower platelet count, and mild renal involvement.

The significance of ADAMTS13 deficiency in adult thrombotic microangiopathy (TMA) remains controversial. In an attempt to define the characteristics of adult TMA with severe ADAMTS13 deficiency, we determined 2 groups of patients on the basis of ADAMTS13 activity (undetectable or detectable). Clinical presentation, laboratory values, autoimmune manifestations, and outcome were compared between the groups. Patients were included retrospectively from 12 centers. All fulfilled the diagnosis criteria of TMA. Patients with a history of transplantation, cancer and chemotherapy, and Centers for Disease Control and Prevention (CDC) stage C human immunodeficiency virus (HIV) infection were not included. Forty-six patients were included. Thirty-one patients had an undetectable ADAMTS13 activity (<5%), and the remaining 15 patients had ADAMTS13 activity of >25%. Severe ADAMTS13 deficiency was associated with a plasmatic inhibitor in 17 cases (55%), suggesting an immune-mediated mechanism. Patients with undetectable ADAMTS13 were more frequently of Afro-Caribbean origin than patients with detectable ADAMTS13 activity (48.4% vs 13.3%, respectively; p = 0.03). As opposed to patients with detectable ADAMTS13 activity, patients with severe ADAMTS13 deficiency displayed various autoimmune manifestations that consisted of nondestructive polyarthritis (4 cases) associated in 1 case with malar rash and extramembranous glomerulonephritis, discoid lupus (3 cases), and autoimmune endocrinopathies, Raynaud phenomenon, and sarcoidosis-like disease (1 case each). In patients with severe ADAMTS13 deficiency, antinuclear antibodies, anti-double-stranded DNA antibodies, and anticardiolipin antibodies were positive in 22 (71%) cases, 3 (9.7%) cases, and 1 (3.2%) case, respectively. One patient fulfilled the criteria for the diagnosis of systemic lupus erythematosus. During follow-up, 1 patient with severe ADAMTS13 deficiency developed antinuclear antibodies, and 3 others developed anti-double-stranded DNA antibodies, in association with neurologic manifestations and anticardiolipin antibodies in 1 case. Patients with severe ADAMTS13 deficiency also had a lower platelet count (12 x 10(9)/L; range, 2-69 x 10(9)/L) and less severe renal failure (estimated glomerular filtration rate: 78 mL/min; range, 9-157 mL/min) than patients with detectable ADAMTS13 activity (49.5 x 10(9)/L; range, 6-103 x 10(9)/L; p = 0.0004, and 15.8 mL/min; range, 5.6-80 mL/min; p < 0.0001, respectively). End-stage renal failure occurred in 1 patient with severe ADAMTS13 deficiency and in 3 patients with detectable ADAMTS13 activity (3.2% vs 21.4%, respectively; p = 0.08). Flare-up and relapse episodes and survival were comparable between the groups. Taken together, these data indicate that adult idiopathic thrombotic thrombocytopenic purpura, as defined by severe ADAMTS13 deficiency, may occur preferentially in a particular ethnic group, and is characterized by severe thrombocytopenia, mild renal involvement, and a wide spectrum of autoimmune manifestations that may be completed during follow-up. Indeed, apparently idiopathic thrombotic thrombocytopenic purpura may be considered a specific autoimmune disease.

Immunoproliferative small intestinal disease associated with Campylobacter jejuni.

BACKGROUND: Immunoproliferative small intestinal disease (also known as alpha chain disease) is a form of lymphoma that arises in small intestinal mucosa-associated lymphoid tissue (MALT) and is associated with the expression of a monotypic truncated immunoglobulin alpha heavy chain without an associated light chain. Early-stage disease responds to antibiotics, suggesting a bacterial origin. We attempted to identify a causative agent. METHODS: We performed polymerase chain reaction (PCR), DNA sequencing, fluorescence in situ hybridization, and immunohistochemical studies on intestinal-biopsy specimens from a series of patients with immunoproliferative small intestinal disease. RESULTS: Analysis of frozen intestinal tissue obtained from an index patient with immunoproliferative small intestinal disease who had a dramatic response to antibiotics revealed the presence of Campylobacter jejuni. A follow-up retrospective analysis of archival intestinal-biopsy specimens disclosed campylobacter species in four of six additional patients with immunoproliferative small intestinal disease. CONCLUSIONS: These results indicate that campylobacter and immunoproliferative small intestinal disease are associated and that C. jejuni should be added to the growing list of human pathogens responsible for immunoproliferative states.