Claudia Wehr

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.

CLL B-cell receptors can recognize themselves: alternative epitopes and structural clues for autostimulatory mechanisms in CLL

To the editor: Chronic lymphocytic leukemia (CLL) may be driven by antigen recognition through the B-cell receptor (BCR).[1][1][⇓][2][⇓][3][⇓][4][⇓][5][⇓][6]–[7][7] A recent paper in Nature [8][8] suggested a new mechanism for such antigenic drive by functionally characterizing an

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.

Bronchoalveolar lavage cytology resembles sarcoidosis in a subgroup of granulomatous CVID

To the Editor: We read with great interest the article by Bouvry et al. [1] regarding similarities and differences between interstitial lung disease (ILD) in granulomatous common variable immunodeficiency (CVID) and sarcoidosis. In this retrospective study, differential bronchoalveolar lavage (BAL) cytology was analysed in 14 patients with granulomatous CVID and ILD. The authors found BAL lymphocytosis (>20%) in 11 out of 14 patients and a mean±sd proportion of BAL lymphocytes of 37.3±15.3%. Unlike the sarcoidosis group (5.3±4.0), the CD4/CD8 ratio was low in the analysed patients with granulomatous CVID and ILD (1.6±1.1, n=10) and even <1 in half of the patients (n=5). Bouvry et al. [1] concluded that there are significant differences in differential BAL cytology between sarcoidosis and granulomatous CVID. We therefore retrospectively analysed a subgroup of 11 CVID patients (seven …

B-cell signaling in persistent polyclonal B lymphocytosis (PPBL).

Persistent polyclonal B lymphocytosis (PPBL) is a benign hematological disorder characterized by a selective expansion of circulating polyclonal marginal zone (MZ)‐like B cells. Previous reports demonstrated that cases of PPBL showed poor activation, proliferation and survival of B cells in vitro, yet the underlying defect remains unknown. Here we report for the first time an attenuated activation of the canonical NF‐κB (nuclear factor of kappa light polypeptide gene enhancer in B cells) and mitogen‐activated protein kinase/extracellular signal‐regulated kinase pathway after CD40 stimulation. This defect was selective, as alternative NF‐κB signaling after CD40 stimulation and both B‐cell receptor‐ and Toll‐like receptor 9‐mediated activation remained unaffected. Reduced canonical NF‐κB activation resulted in decreased IκBα and CD40 expression in resting cells. In PPBL patients, expression of Bcl‐xL in MZ‐like B cells did not increase upon activation, consistent with the high apoptosis rates of PPBL‐derived B cells that were observed in vitro. The B‐cell phenotype of mice with selective knockouts of early components of the CD40 signaling pathway resembles PPBL, but sequencing corresponding genes in sorted MZ‐like B cells of PPBL patients did not reveal relevant genetic alterations. Nevertheless, the frequently observed mutations in early signaling components of the NF‐κB pathway in MZ lymphomas underline the relevance of our findings for the pathogenesis of PPBL.

Recurrence of persistent polyclonal B lymphocytosis (PPBL) after rituximab treatment

Dear Editor, Persistent polyclonal B lymphocytosis (PPBL) is a rare entity with a polyclonal increase of marginal zone-like B lymphocytes in the peripheral blood [1, 2], most prevalent in smoking middle-aged women [3]. Patients display elevated immunoglobulin M (IgM) and sometimes decreased IgG levels in the serum [4–6]. Splenomegaly and/or polyclonal lymphocytic infiltration of the bone marrow may be present [7, 8]. The disease has been associated with HLA-DR7 positivity and chromosomal abnormalities [6], but its etiology remains elusive. Herein, we report its recurrence after rituximab treatment, revealing interesting aspects of its putative pathophysiology. A 44-year-old Caucasian womanwith a history of Sudeck’s dystrophy and hysterectomy presented with epigastric pain. The patient was an active smoker. Awork-up revealed splenomegaly (3.6×16.5 cm) in the absence of enlarged lymph nodes. A differential blood count showed normal leukocyte count (9440/μl) with lymphocytosis (4863/μl, normal 1000– 2800/μl), and blood smear showed atypical, agranular large lymphocytes with bilobated nuclei (Fig. 1a). IgM was elevated (3.18 g/l, normal 0.4–2.3 g/l, Fig. 1b) without monoclonal bands in immunofixation, and IgG was reduced (4.09 g/l, normal 7–16 g/l). A bone marrow biopsy showed normal hematopoiesis and mild lymphocytosis without blasts or light chain restriction. Relative lymphocytosis in the peripheral blood was traced back to a B lymphocytosis (3457/μl, normal 100–500/μl, Fig. 1c) with no detectablemonoclonality in flow cytometry and IgH clonality analysis (Fig. 1d). The patient was HLA-DR7 negative. Albeit a watch-and-wait strategy is generally indicated in this situation, the patient was treated four times with 375 mg/ m rituximab resulting in the normalization of her spleen size (3.7×10.8 cm) and IgM level (2.1 g/l), as well as an eradication of her peripheral blood B lymphocytes (0/μl). Eighteen months after rituximab treatment, her B cell counts were back to normal (307/μl) and a mild polyclonal IgM elevation had returned (2.47 g/l). B cell numbers continued to rise over the next months (Fig. 1c), lymphocytes with bilobated nuclei reappeared, and B cell subpopulation analysis 2 years after the rituximab treatment showed an expansion of marginal zone-like B lymphocytes in the peripheral blood (52.1 % of B cells, normal <30.8 %) indicating recurrence of PPBL. However, her spleen size was still normal. FISH analysis revealed one or two 3q gains in 3.5 % of B cells, respectively (Fig. 1e, cutoffs for non-B cells 0.5–1.0 %). The recurrence of the PPBL phenotype after eradication of the recirculating B cell pool is remarkable and gives rise to various speculations on the etiology of PPBL. Given the high cellular burden in PPBL, an insufficient eradication and re-expansion of affected B cells in peripheral tissues is a possible explanation; however, the eradication from peripheral blood was complete. Alternatively, as CD20 expression is C. Wehr : L. Houet : S. Gutenberger :K. Warnatz (*) Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, University of Freiburg, Breisacherstrasse 117, 79106 Freiburg, Germany e-mail: klaus.warnatz@uniklinik-freiburg.de