Arnold I. Levinson

Practice parameter for the diagnosis and management of primary immunodeficiency

TABLE OF CONTENTS I. Preface S1 II. Executive Summary S2 III. Algorithms S7 IV. Summary Statements S14 V. General Considerations S20 VI. Humoral Immunodeficiencies S24 VII. Cellular Immunodeficiencies S30 VIII. Combined Immunodeficiencies S33 IX. Phagocytic Cell Disorders S40 X. Complement Deficiencies S43 XI. Acknowledgments S45 XII. References S45 XIII. Appendix S61

Granulomatous-lymphocytic interstitial lung disease (GLILD) in common variable immunodeficiency (CVID)

Infectious complications of the lung occur quite frequently in patients with common variable immunodeficiency (CVID), a clinical syndrome that represents a primary immunodeficiency. However, there appears to be noninfectious pulmonary complications in association with CVID as well, and recently the term granulomatous-lymphocytic interstitial lung disease (GLILD) has been created to describe these noninfectious, diffuse lung disease complications that develop in CVID patients. They exhibit both granulomatous and lymphoproliferative histologic patterns, consisting of lymphocytic interstitial pneumonia (LIP), follicular bronchiolitis, and lymphoid hyperplasia. There are many unanswered questions surrounding this relatively unstudied entity. In an attempt to answer some of these questions, this review discusses in detail pathologic and clinical features of GLILD and its proposed pathogenesis with a particular attention to potential role of human herpesvirus 8 (HHV-8). Lastly, therapeutic approach is discussed to generate novel treatment strategy to better care for a subgroup of CVID patients afflicted with this entity.

The nexus between atopic disease and autoimmunity: a review of the epidemiological and mechanistic literature‡

There has been considerable interest in defining the relationship between the expression of allergic and autoimmune diseases in populations of patients. Are patients with autoimmune disease ‘protected’ from developing allergic (immunoglobulin E‐mediated) diseases? Does the establishment of an atopic phenotype reduce the risk of the subsequent development of autoimmune diseases? Although there are clinical studies addressing this question, methodological problems, particularly in identification of atopic subjects, limits their usefulness. Moreover, an immune‐based explanation of the observed epidemiological findings has relied on a paradigm that is currently undergoing increased scrutiny and modification to include newly defined effector cell subsets and the interaction between genetic and environmental factors, such as early endotoxin or mycobacterial exposure. To address this question, we reviewed a series of clinical reports that addressed coincidence or co‐prevalence of atopy with four autoimmune diseases: psoriasis, rheumatoid arthritis, multiple sclerosis and type I diabetes mellitus. We present a model whereby active T helper type 1 (Th1) inflammation may suppress the development of atopy, and atopy may suppress the severity but not necessarily the onset of autoimmunity, and then discuss our model in the context of mechanisms of adaptive immunity with particular reference to the Th1/Th2 paradigms. Because the ultimate goal is to ameliorate or cure these diseases, our discussion may help to predict or interpret unexpected consequences of novel therapeutic agents used to target autoimmune or atopic diseases.

Effect of the REG1 anticoagulation system versus bivalirudin on outcomes after percutaneous coronary intervention (REGULATE-PCI): A randomised clinical trial

BACKGROUND REG1 is a novel anticoagulation system consisting of pegnivacogin, an RNA aptamer inhibitor of coagulation factor IXa, and anivamersen, a complementary sequence reversal oligonucleotide. We tested the hypothesis that near complete inhibition of factor IXa with pegnivacogin during percutaneous coronary intervention, followed by partial reversal with anivamersen, would reduce ischaemic events compared with bivalirudin, without increasing bleeding. METHODS We did a randomised, open-label, active-controlled, multicentre, superiority trial to compare REG1 with bivalirudin at 225 hospitals in North America and Europe. We planned to randomly allocate 13,200 patients undergoing percutaneous coronary intervention in a 1:1 ratio to either REG1 (pegnivacogin 1 mg/kg bolus [>99% factor IXa inhibition] followed by 80% reversal with anivamersen after percutaneous coronary intervention) or bivalirudin. Exclusion criteria included ST segment elevation myocardial infarction within 48 h. The primary efficacy endpoint was the composite of all-cause death, myocardial infarction, stroke, and unplanned target lesion revascularisation by day 3 after randomisation. The principal safety endpoint was major bleeding. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, identifier NCT01848106. The trial was terminated early after enrolment of 3232 patients due to severe allergic reactions. FINDINGS 1616 patients were allocated REG1 and 1616 were assigned bivalirudin, of whom 1605 and 1601 patients, respectively, received the assigned treatment. Severe allergic reactions were reported in ten (1%) of 1605 patients receiving REG1 versus one (<1%) of 1601 patients treated with bivalirudin. The composite primary endpoint did not differ between groups, with 108 (7%) of 1616 patients assigned REG1 and 103 (6%) of 1616 allocated bivalirudin reporting a primary endpoint event (odds ratio [OR] 1·05, 95% CI 0·80-1·39; p=0·72). Major bleeding was similar between treatment groups (seven [<1%] of 1605 receiving REG1 vs two [<1%] of 1601 treated with bivalirudin; OR 3·49, 95% CI 0·73-16·82; p=0·10), but major or minor bleeding was increased with REG1 (104 [6%] vs 65 [4%]; 1·64, 1·19-2·25; p=0·002). INTERPRETATION The reversible factor IXa inhibitor REG1, as currently formulated, is associated with severe allergic reactions. Although statistical power was limited because of early termination, there was no evidence that REG1 reduced ischaemic events or bleeding compared with bivalirudin. FUNDING Regado Biosciences Inc.

Toll-like receptor 7-induced naive human B-cell differentiation and immunoglobulin production.

BACKGROUND Toll-like receptors contribute to the establishment of adaptive immune responses. OBJECTIVE The reported studies were conducted to examine the effects of the Toll-like receptor (TLR)-7 ligand, resiquimod, on human naive B-cell differentiation. METHODS Naive human B cells were cultured with resiquimod in the presence or absence of IL-2 and IL-10. Secreted IgM and IgG were measured by ELISA, and IL-6, IL-10, and IFN-alpha were measured by a multiplex protein array. Cell proliferation was assessed by measuring [(3)H]thymidine uptake. mRNA for activation-induced cytidine deaminase and I(gamma 1)-C(mu) circle transcripts was measured by means of RT-PCR. RESULTS Resiquimod induced the production of IgM and, to a lesser extent, IgG by naive human B cells in association with the secretion of IL-6 and IL-10, and a weak proliferative response. IL-2 and IL-10 synergized with resiquimod in markedly augmenting resiquimod-induced IgM and IgG production and proliferation. Resiquimod also stimulated production of IgG by B cells isolated from the blood of a patient with the X-linked hyper-IgM syndrome, with a greater response when these cells were costimulated with IL-2 and IL-10. The stimulated naive B cells from healthy volunteers displayed molecular evidence of immunoglobulin class-switch recombination-namely the appearance of activation-induced cytidine deaminase and I(gamma 1)-C(mu) circle transcripts. CONCLUSION Perturbation of TLR-7 on naive human B cells can lead to the induction of immunoglobulin class switch and IgG production in the absence of B-cell receptor cross-linking and CD40-CD40L interaction. The results are relevant to vaccine development and mechanisms by which microbial infection may lead to autoimmunity.

Immunopathogenesis and treatment of myasthenia gravis.

Myasthenia gravis (MG) 4 is a disease of neuromuscular transmission characterized by weakness of striated muscles. The defect in neuromuscular transmission is mediated by autoantibodies which react with nicotinic acetycholine (AChR) receptors at postsynaptic myoneural junctions. In this review, we examine the immunopathogenesis of MG and consider various therapeutic strategies suggested by work in this area as well as by advances in our understanding of immunoregulation and autoimmunity.

Granulomatous-lymphocytic interstitial lung disease associated with common variable immunodeficiency: CT findings.

Purpose To evaluate computed tomography (CT) scans of individuals with granulomatous-lymphocytic interstitial lung disease and common variable immunodeficiency (CVID) to determine if there are imaging features that distinguish this manifestation of CVID from the more usual imaging findings. Materials and Methods A review of the CVID population at our institution identified a series of 5 patients with CVID who had documented granulomatous disease on biopsy specimens. The initial and follow-up CT examinations were reviewed by 2 radiologists, and imaging findings in the chest and abdomen were tabulated by consensus. In addition, a pathologist reviewed histopathologic specimens and clinical presentations and therapeutic interventions were obtained from patient charts. Results In all, 5/5 patients (100%) had widespread pulmonary micronodules with a lower lung zone predominance, 4/5 (80%) had smooth interlobular septal thickening with mid to lower lung zone predominance, 1/5 (20%) had mild bronchiectasis, 4/5 (80%) had multifocal pulmonary consolidation, 5/5 (100%) had thoracic or abdominal lymphadenopathy, 2/5 (40%) had hepatomegaly, 5/5 (100%) had splenomegaly, 1/5 (20%) had nonspecific hypoattenuating splenic lesions, and 2/5 (40%) had nonspecific hypoattenuating renal lesions. The pulmonary nodules and lymphadenopathy commonly tended to wax and wane in severity over time, and more marked disease was often associated with areas of focal consolidation. Conclusion Granulomatous-lymphocytic interstitial lung disease, which can occur in patients with CVID, presents with CT findings distinct from the usual airway abnormalities most commonly associated with CVID.

Immunologic characterization of cerebrospinal fluid lymphocytes: Preliminary report

Cellular immunocompetence of cerebrospinal fluid lymphocytes was investigated in several neurologic diseases. Microtechniques were developed to enable determination of E-rosetting capacity and phytohemagglutinin responsiveness of scant numbers of cells present in the cerebrospinal fluid specimens studied. Although most individuals had phytohemagglutinin-responsive cells in their CSF, reactivity was somewhat less than that found simultaneously in their blood. Three of eight patients had comparable percentages of E rosettes in their blood and CSF. In the remainder, the values differed significantly. Although preliminary, these results illustrate a new approach to immunologic characterization of CSF lymphocytes in diseases.

The immunobiology of human Fcγ receptors on hematopoietic cells and tissue macrophages

Abstract The ability to identify and remove potentially dangerous foreign organisms and proteins is critical to the survival of a species. In humans, IgG antibodies serve to recognize such foreign antigens and to facilitate their removal. The latter process involves several hematopoietic cells, including those of the macrophage phagocytic system, which express Fcγ receptors. These receptors specifically recognize the Fc domain of IgG antibody. On the surface of hematopoietic cells these Fcγ receptors mediate cell attachment and stimulate several signal transduction events, including those which lead to phagocytosis. Moreover, their perturbation can lead to the generation and release of mediators and enzymes involved in inflammation and in the pathogenesis of autoimmune diseases.

Humoral immune responses within the human central nervous system following systemic immunization.

We investigated sequential humoral immune responses in the CSF and blood of 6 stable multiple sclerosis (MS) patients without decreases in the blood-brain barrier. Anti-tetanus toxoid antibodies (anti-TT Ab) increased to a similar relative degree within the CSF and blood starting within 2 weeks after subcutaneous booster injection of TT. In 3 of 4 subjects, CSF lymphocytes obtained at 2 weeks secreted anti-TT Ab to the same degree as autologous blood lymphocytes when cultured with pokeweed mitogen. These findings suggest a prompt antibody response within the CSF to systemically administered antigen, not due to diffusion from the serum, with active trafficking of TT-sensitized lymphocytes into the central nervous system.