Ruth Dräger

Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency

No genetic defect is known to cause common variable immunodeficiency (CVID), a heterogeneous human disorder leading to adult-onset panhypogammaglobulinemia. In a search for CVID candidate proteins, we found four of 32 patients to lack ICOS, the “inducible costimulator” on activated T cells, due to an inherited homozygous deletion in the ICOS gene. T cells from these individuals were normal with regard to subset distribution, activation, cytokine production and proliferation. In contrast, naive, switched and memory B cells were reduced. The phenotype of human ICOS deficiency, which differs in key aspects from that of the ICOS−/− mouse, suggests a critical involvement of ICOS in T cell help for late B cell differentiation, class-switching and memory B cell generation.

Presence of IgE antibodies to bovine serum albumin in a patient developing anaphylaxis after vaccination with human peptide-pulsed dendritic cells

Abstract Dendritic cells are professional antigen-presenting cells that can be generated in vitro either from monocytes or from CD34+ peripheral blood progenitor cells by using recombinant cytokines. These cells have potential implications for immunotherapeutic approaches in the treatment of cancer and other diseases. We have conducted a phase I study in melanoma patients using peptide-pulsed dendritic cells cultured in medium supplemented with 10% fetal calf serum (FCS) and a cocktail of cytokines. Peptide-pulsed dendritic cells were injected intravenously at 2-week intervals. Here we report on a case of type I hypersensitivity anaphylactic reaction after repetitive vaccination with autologous peptide-pulsed cells. Pre-vaccination and post-vaccination serum samples were evaluated for the presence of antibodies to FCS and bovine serum albumin (BSA). A retrospective study in 7 patients vaccinated with FCS-cultured dendritic cells demonstrated the presence of IgG and IgM antibodies to FCS and BSA after vaccination in 6 out of 7 patients. However, IgE antibodies were absent in all patients with the exception of the patient developing anaphylaxis. The patients serum was demonstrated to contain a strong IgE response directed against BSA. In contrast, 2 patients vaccinated with dendritic cells cultured under serum-free conditions developed no antibodies to FCS and BSA after repetitive vaccination. We suggest that patients can be sensitized with an IgE response against BSA leading to anaphylactic reactions. On the basis of these data, dendritic cells cultured in autologous serum or under serum-free conditions are recommended for therapeutic applications in vivo.

Expansion of CD19hiCD21lo/neg B Cells in Common Variable Immunodeficiency (CVID) Patients with Autoimmune Cytopenia

Common variable immunodeficiency (CVID) is characterized by a severe hypogammaglobulinemia. While the clinical picture is dominated by recurrent respiratory and gastrointestinal infections, a subgroup of up to 30% of the patients develops additional autoimmune phenomena, including thrombocytopenia and autoimmune hemolytic anemia. So far no classification allowed a prediction of the coincidence of immunodeficiency and autoimmunity. Here, we propose the size of the peripheral CD19(hi)CD2(lo/neg) B cell pool as a marker for CVID patients with autoimmune cytopenia and splenomegaly. Interestingly similar B cell populations are also found in patients with SLE and may not only be an epiphenomenon of the disease.

Quantification of IgM and IgA Anti-Pneumococcal Capsular Polysaccharides by a New ELISA Assay: a Valuable Diagnostic and Prognostic Tool for Common Variable Immunodeficiency

PurposeExisting ways of assessing CVID patients at risk of pulmonary infections are not universally accepted. The need to identify additional prognostic factors allowed us to evaluate the anti-polysaccharide IgA and IgM responses in 125 CVID patients immunized with the 23-valent pneumococcal polysaccharide (PS) vaccine (Pneumovax®).MethodsWe used a new anti-PS23 IgM and IgA ELISA assay, which evaluates a global response to all 23 polysaccharides contained in Pneumovax®.ResultsAnti-PS23 IgM and/or IgA antibodies were detectable in a minority of CVID patients. Antibody responses were correlated to B cell subpopulations and serum immunoglobulin concentrations. The non responders had a higher incidence of pneumonia and bronchiectasis and responders had the lowest incidence of respiratory complications.ConclusionsThis new ELISA assay allows for studying vaccine response in patients on Ig replacement therapy. This test also is an additional method of evaluation of specific antibody responses representing a valuable contribution to identify prognostic marker in CVID patients.

Ill-Defined Germinal Centers and Severely Reduced Plasma Cells are Histological Hallmarks of Lymphadenopathy in Patients with Common Variable Immunodeficiency

Given the severely reduced numbers of circulating class-switched memory B cells and plasmablasts in patients with common variable immunodeficiency (CVID) the germinal center (GC) reaction as the source of both populations is expected to be disturbed in many CVID patients. Therefore immunohistochemical studies were performed on lymph node (LN) biopsies from ten CVID patients with benign lymphoproliferation. According to the Sander classification the majority of patients presented with reactive lymphoid hyperplasia (7/10), 6/10 showed granulomatous inflammation. All cases showed some normal GCs but in 9/10 these concurred to a varying degree with hyperplastic, ill-defined GCs in the same LN. The percentage of ill-defined GCs correlated significantly with the percentage of circulating CD21low B cells suggesting a common origin of both immune reactions. In 9/10 CVID LNs significantly higher numbers of infiltrating CD8+ T cells were found in GCs of CVID patients compared to controls, but no HHV-8 and only in 2/10 LNs EBV infection was detected. Class switched plasma cells (PCs) were severely reduced in 8/10 LNs and if present, rarely found in the medulla of the LN. Based on the presence of large GCs in all examined patients, the reduction of circulating memory B cells and PCs points towards a failure of GC output rather than GC formation in CVID patients with lymphadenopathy.

Monocyte Differentiation and Accessory Function: Different Effects on the Proliferative Responses of an Autoreactive T Cell Clone as Compared to Alloreactive or Antigen-Specific T Cell Lines and Primary Mixed Lymphocyte Cultures

An autoreactive T cell clone derived from a patient with reactive arthritis, two alloreactive T cell lines, two antigen-specific T cell lines and allogeneic resting T cells were analyzed for their responses to monocytes and macrophages derived from monocytes by in vitro differentiation. The autoreactive T cell clone strongly proliferated in response to fresh monocytes and to macrophages derived from a 7 day culture, but only poorly to monocytes cultured for 2 days. In contrast, alloreactive and antigen-specific T cell lines proliferated to all stimulatory cells equally well. Finally, primary mixed lymphocyte reactions could be stimulated by both fresh and 2-day cultured monocytes, but not by in vitro derived macrophages. The impaired response of the autoreactive T cell clone to 2-day cultured monocytes could not be attributed to reduced expression of several well-defined surface molecules nor to induction of nonresponsiveness. Neither allogeneic monocytes nor cytokines (IL-1, IL-2, IL-4, IL-6) could correct the defective response of the autoreactive T cell clone. However, preculture of monocytes in the presence of interferon-gamma, IL-1, IL-4 or IL-6 retained their stimulatory capacity. Our interpretation of the selectively impaired response of the autoreactive T cell clone is that it most likely recognizes a differentiation-dependent monocyte/macrophage-specific peptide.

Disseminated tuberculosis in a patient with idiopathic CD4+ lymphocytopenia

collagen have been identified in RP, suggesting a Th 1-type autoimmune disease producing TNF; and (ii) TNFhas been found in vitro to induce increased synthesis of matrix-degrading proteinases from chondrocytes, resulting in damage in RP [7]. Few reports have, in fact, described previously improvement of auricular, nasal, ocular and joint complications in patients, who were unresponsive to cytotoxic drugs, after the initiation of infliximab [8, 9]. Moreover, Mpofu et al. [7] and Subrahmanyam et al. [10] have also reported a patient with recalcitrant respiratory tract localizations, in whom infliximab led to resolution of active disease. Our case is also original in that our patient with refractory RP-related aortic involvement (aneurysm of the abdominal aorta and active abdominal aortitis) was successfully given infliximab. We therefore suggest that infliximab may be an effective therapy for RP-related aortic involvement that is unresponsive to conventional therapy. In fact, at 3-year follow-up, our patient was symptom free and CT scan revealed no deterioration of aortic impairment. Moreover, our patient did not develop adverse effect (e.g. infectious complications) related to infliximab.