IntroductionCommon variable immunodeficiency (CVID) is the most common primary immunodeficiency in adults. 1 Recurrent bacterial infections of the respiratory tract are the clinical hallmark present in nearly all patients. 2 In addition, up to 40% of the patients show gastrointestinal disease, concomitant lymphoproliferative disorders, autoimmune phenomena, or granulomatous inflammation. 2 The pathogenic understanding of antibody deficiency in humans has always been hampered by the great heterogeneity of the syndrome. 3 In 1966, Rosen and Janeway started to group antibody deficiencies by their mode of inheritance. 4 In 1973, Cooper included the clinical course and serum immunoglobulin levels, thereby separating hyper-IgM syndromes and selective IgA deficiency. 5 The remaining group of still very heterogeneous antibody deficiencies was termed CVID. Consecutive attempts to subclassify CVID by B-cell function in vitro 6,7 failed to reach diagnostic acceptance because of laborious and poorly standardized procedures and a lack of clinical relevance.In 2002, we and others suggested a flow cytometric classification of CVID according to the B-cell phenotype. 8,9 The abnormalities of circulating B cells in patients with CVID had already been recognized earlier, 10 but only with the ease and the broad availability of flow cytometry was a widespread and systematic analysis of these aberrations possible. The Freiburg classification divided patients into 3 groups by analyzing the expression of IgM, IgD, CD27 and CD21. 8 Group 1 was characterized by a severe reduction of switched memory B cells (IgD Ϫ IgM Ϫ CD27 ϩ less than 0.4% of lymphocytes), while group 2 representing 25% of the analyzed CVID patients exhibited nearly normal numbers of class-switched memory B cells, suggesting a post germinal center defect. The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. Methods PatientsAll patients were diagnosed as having CVID based on the European Society for Immunodeficiencies/Pan-American Group for Immunodeficiency (ESID/PAGID) criteria, 11 including a marked decrease of IgG (at least 2 standard deviations [SDs] below the mean for age) and a marked decrease in at least one of the isotypes IgM or IgA, the onset of clinical significant immunodeficiency at greater than 2 years of age, and the exclusion of defined causes of hypogammaglobulinemia (see also www.esid.org). Not all patients have been evaluated for absent isohemagglutinins and/or poor response to vaccines. For the final evaluation of B-cell phenotyping, the following exclusion criteria were adopted: patients younger than 6 years of age at the time of flowcytometric evaluation, patients on immunosuppressive treatment, patients suffering currently from malignancies, and patients with less than 1% peripheral B cells. Altogether, 303 patients of origi...

Background. A 23-valent unconjugated pneumococcal polysaccharide vaccine (23vP), routinely administered at the age of 65, has limited effectiveness, and revaccination induces attenuated antibody responses. It is not known whether pneumococcal polysaccharide-protein conjugated vaccines (PCV), although highly effective in infants, offer any immunological advantages over 23vP in adults.Methods. We immunized adults with schedules combining both PCV and 23vP and investigated B-cell responses to establish whether PCV7 (a 7-valent PCV) induced T-dependent responses in adults, to assess the role of memory B cells in 23vP-induced antibody hyporesponsiveness, and to identify the B-cell subtypes involved.Results. A single dose of PCV7 induced significant increases in serotype-specific memory B-cell populations in peripheral blood indicating a T-dependent response. Conversely, immunization with 23vP resulted in a decrease in memory B-cell frequency. Furthermore, memory B-cell responses to subsequent immunization with PCV7, when given after 23vP, were attenuated. Notably, B1b cells, a subset important in protecting mice against pneumococci, were also depleted following immunization with 23vP in humans.Conclusions. This study indicates that PCV7 may have an immunological advantage over 23vP in adults and that 23vP-induced depletion of memory and B1b-cell subsets may provide a basis for antibody hyporesponsiveness and the limited effectiveness of 23vP.Clinical Trials Registration. ISRCTN: 78768849.

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Summary Common variable immunodeficiency disorders (CVID) are a group of heterogeneous conditions that have in common primary failure of B cell function, although numerous T cell abnormalities have been described, including reduced proliferative response and reduced regulatory T cells. This study compared the T cell phenotype of CVID patients subdivided into clinical phenotypes as well as patients with partial antibody deficiencies [immunoglobulin (Ig)G subclass deficiency and selective IgA deficiency], X‐linked agammaglobulinaemia (XLA) and healthy and disease controls. Absolute numbers of T cell subpopulations were measured by four‐colour flow cytometry: naive T cells, central and effector memory and terminally differentiated (TEM) T cells, using CD45RA and CCR7 expression. Early, intermediate and late differentiation status of T cells was measured by CD27/CD28 expression. Putative follicular T cells, recent thymic emigrants and regulatory T cells were also assessed. Significant reduction in naive CD4 T cells, with reduced total CD4 and recent thymic emigrant numbers, was observed in CVID patients, most pronounced in those with autoimmune cytopenias or polyclonal lymphoproliferation. These findings suggest a lack of replenishment by new thymically derived cells. CD8 naive T cells were reduced in CVID patients, most significantly in the autoimmune cytopenia subgroup. There was a reduction in early differentiated CD4 and CD8 T cells and increased CD8 TEM in the CVID patients, particularly autoimmune cytopenia and polyclonal lymphoproliferation subgroups, suggesting a more activated T cell phenotype, due perhaps to an antigen‐driven process. XLA patients had significantly reduced putative follicular T cells, which may depend on B cells for survival, while no significant alterations were observed in the T cells of those with IgG subclass deficiency or selective IgA deficiency.

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In adults, vaccination schedules combining PCV7 and 23vP do not provide improved immunogenicity over the use of a single dose of 23vP for most of the serotypes contained in PCV7.

Although clinical and laboratory evidence support roles for both staphylococcal infection and environmental allergens in the pathogenesis of atopic dermatitis, human studies have largely considered these variables independently. We sought to test the hypothesis that staphylococcal superantigen influences the allergen-specific T cell response. We first mapped a Der p 1 epitope and used HLA DRB1*1501 class II tetramer-based cell sorted populations to show that specific CD4 ؉ T cells were able to recognize the peptide presented by HLA DR-matched keratinocytes. We observed that staphylococcal enterotoxin B (SEB) enhanced the IL-4 Der p 1-specific T cell response. This response was mediated by two synergistic mechanisms: first, SEB-induced IFN-␥ promoted class II and intercellular adhesion molecule-1 expression by presenting keratinocytes; and second, SEB-induced IL-4 directly amplified allergen-specific CD4 ؉ T cell production of many cytokines. We propose that handling of staphylococcal infection is a critical step in the amplification of the allergen-specific T cell response, linking two common disease associations and with implications for the prevention and treatment of atopic disease.T here is convincing evidence that allergic reactivity to environmental challenge has a role in the pathogenesis of atopic dermatitis (AD). For example, the histology of AD shares many features with classic allergic contact delayed-type hypersensitivity, including spongiosis and a dominant T cell inflammatory infiltrate that is distributed predominantly in a dermal, and to a lesser extent epidermal pattern. Approximately 80% of individuals with AD have circulating specific IgE recognizing one or more of house dust mite, cat, dog, grass, and other ubiquitous environmental allergens (1). In many studies, allergen-specific CD4 ϩ and CD8 ϩ T cells have been documented to be present in the peripheral blood and lesional skin of affected individuals and to produce diverse cytokines but with a frequent T helper 2 (Th2) dominance (2, 3). House dust mite extract application to the skin of individuals with AD can reproduce eczematous changes (4, 5), and allergen avoidance has been shown by some to be partially effective (6, 7). Keratinocytes have been shown to up-regulate HLA class II and intercellular adhesion molecule-1 (ICAM-1) in AD and other inflammatory dermatoses (8, 9) and also in response to injection of IFN-␥ into normal skin (10). However, in isolation, allergic reactivity to an environmental challenge does not explain all of the features of AD. Twenty percent of affected individuals do not generate IgE responses to such ubiquitous proteins, and it is unclear why disease incidence changes during age and between different geographical regions. The risk of disease is clearly influenced by genetic susceptibility factors, some of which affect the immune response, e.g., polymorphisms of the Fc R1 and IL-4R genes (11-13). However, it is becoming increasingly clear from the genetic studies that skin-specific genes, determining variables s...

Summary Recent reports have described reduced populations of CD27+ + + + memory B cells and increased percentages of undifferentiated B cells in peripheral blood of patients with common variable immunodeficiency (CVID). This work has prompted two attempts to classify CVID based on rapid flow cytometric quantification of peripheral blood memory B cells and immature B cells. Evidence to support the hypothesis that such in vitro B cell classification systems correlate with clinical subtypes of CVID is being sought. For the classification to be useful in routine diagnosis, it is important that the flow cytometric method can be used without prior separation of peripheral blood mononuclear cells (PBMC). We have examined 23 CVID patients and 24 controls, using both PBMC and whole blood, and find an excellent correlation between these methods. The reproducibility of the method was excellent. We classified the CVID patients by all three of the existing classifications, including secretion of immunoglobulin by B cells in vitro as described by Bryant, as well as the more recent flow cytometric classification methods. Only one patient changed classification as a result of using whole blood.