Defective Antibody Production Research Articles

Is dosing of therapeutic immunoglobulins optimal? A review of a three-decade long debate in europe.

The consumption of immunoglobulins (Ig) is increasing due to better recognition of antibody deficiencies, an aging population, and new indications. This review aims to examine the various dosing regimens and research developments in the established and in some of the relevant off-label indications in Europe. The background to the current regulatory settings in Europe is provided as a backdrop for the latest developments in primary and secondary immunodeficiencies and in immunomodulatory indications. In these heterogeneous areas, clinical trials encompassing different routes of administration, varying intervals, and infusion rates are paving the way toward more individualized therapy regimens. In primary antibody deficiencies, adjustments in dosing and intervals will depend on the clinical presentation, effective IgG trough levels and IgG metabolism. Ideally, individual pharmacokinetic profiles in conjunction with the clinical phenotype could lead to highly tailored treatment. In practice, incremental dosage increases are necessary to titrate the optimal dose for more severely ill patients. Higher intravenous doses in these patients also have beneficial immunomodulatory effects beyond mere IgG replacement. Better understanding of the pharmacokinetics of Ig therapy is leading to a move away from simplistic “per kg” dosing. Defective antibody production is common in many secondary immunodeficiencies irrespective of whether the causative factor was lymphoid malignancies (established indications), certain autoimmune disorders, immunosuppressive agents, or biologics. This antibody failure, as shown by test immunization, may be amenable to treatment with replacement Ig therapy. In certain immunomodulatory settings [e.g., idiopathic thrombocytopenic purpura (ITP)], selection of patients for Ig therapy may be enhanced by relevant biomarkers in order to exclude non-responders and thus obtain higher response rates. In this review, the developments in dosing of therapeutic immunoglobulins have been limited to high and some medium priority indications such as ITP, Kawasaki’ disease, Guillain–Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, myasthenia gravis, multifocal motor neuropathy, fetal alloimmune thrombocytopenia, fetal hemolytic anemia, and dermatological diseases.

Objawy kliniczne hipogammaglobulinemii u niemowląt i małych dzieci – znaczenie diagnostyczne „10 Objawów Ostrzegawczych Pierwotnego Niedoboru Odporności”

IntroductionSymptomatology of primary immunodeficiencies (PIDs) with antibody production defects in children is most frequently associated with infections, but allergic, autoimmune and lymphoproliferative disorders may be a leading manifestation. “10 Warning Signs of Primary Immunodeficiency” have been elaborated as an assistance for physicians helpful in suspicion of a disease. Aim of the studyTo define the most frequent manifestation of antibody production defects in infants and young children as well as an attempt to correlate of diagnostic recommendations in “10 Warning Signs of Primary Immunodeficiency” with symptoms presented by patients with hypogammaglobulinemia. Materials and methodsA retrospective chart review of 50 cases: 34 boys and 16 girls, aged from 3 to 24 months, in whom a diagnosis of hypogammaglobulinemia had been established based on defective production of one or more serum immunoglobulin isotypes. ResultsInfections of different organ location were noted in all the hypogammaglobulinemic children studied and among them the most prevalent (in 98% of the children) were respiratory tract infections that in 84% of cases required hospitalization. Infections were also located in the gastrointestinal and urinary tract, hip joint and meninges or manifested as sepsis. The next frequent category of clinical symptoms, present in 66% of the children studied, were allergic diseases. A positive family history of PID was noted in 20% of cases. ConclusionsAwareness of primary immunodeficiency is a task of physicians in ambulatory and hospital health care and concerns both pediatricians as well as other medical specialists. “10 Warning Signs of Primary Immunodeficiency” is a valuable assistance to take measures of diagnosing PIDs in children with infections; however, a diverse manifestation of these disorders indicates the necessity of expanding and updating the recommendations for diagnosing PIDs.

Occurrence of B-cell lymphomas in patients with activated phosphoinositide 3-kinase δ syndrome

Occurrence of B-cell lymphomas in patients with activated phosphoinositide 3-kinase δ syndrome

Evaluation of Antibody Response to Polysaccharide Vaccine and Switched Memory B Cells in Pediatric Patients with Inflammatory Bowel Disease

Background/Aims: Inflammatory bowel disease (IBD) is a chronic disease of the gastrointestinal tract, whose etiologies are still unknown. This study was performed to evaluate the humoral immune response in terms of B cell functions in selected IBD patients. Methods: Eighteen pediatric patients with IBD, including 12 cases of ulcerative colitis (UC) and six with Crohn disease (CD), were enrolled in this study. The pneumococcal vaccine was injected in all patients, and the IgG antibody level to the polysaccharide antigen was measured before and 4 weeks after injection. The B cell switch-recombination process was evaluated. Results: Five patients with IBD (three CD and two UC) had defects in B cell switching, which was significantly higher than in controls (p=0.05). Ten patients had a specific antibody deficiency and exhibited a higher frequency of bacterial infection than the healthy group. The mean increased level of IgG after vaccination was lower in IBD patients (82.9±32.5 μg/mL vs 219.8±59.0 μg/mL; p=0.001). Among the patients who had an insufficient response, no significant difference in the number of switched memory B-cell was observed. Conclusions: A defect in B lymphocyte switching was observed in pediatric IBD patients, and especially in those patients with CD. Owing to an increased risk of bacterial infections in those patients with antibody production defects, pneumococcal vaccination could be recommended. However, not all patients can benefit from the vaccination, and several may require other prophylactic methods. (Gut Liver 2014;8:24-28)

Vaccine strain varicella-zoster virus–induced central nervous system vasculopathy as the presenting feature of DOCK8 deficiency

Vaccine strain varicella-zoster virus–induced central nervous system vasculopathy as the presenting feature of DOCK8 deficiency

X-linked Agammaglobulinemia in Community-acquired Pneumonia Cases Revealed by Immunoglobulin Level Screening at Hospital Admission

In children with primary immunodeficiencies, the onset of symptoms precedes the diagnosis and the initiation of appropriate treatment by months or years. This delay in diagnosis is due to the fact that while these disorders are rare, some of the infections seen in immunodeficient patients are common. Defective antibody production represents the largest group among these disorders, with otitis, sinusitis and pneumonia as the most frequent initial manifestation. We performed a prospective study of humoral immunity in children hospitalized due to community-acquired pneumonia in tertiary care hospital. Out of 254 patients (131 boys, 123 girls, median age 4.5 years) recruited over 3 years, we found 2 boys (age 11 and 21 months) lacking serum immunoglobulins and circulating B cells. Subsequent genetic analysis confirmed diagnosis of X-linked agammaglobulinemia. Despite their immunodeficiency, the pneumonia was uncomplicated in both patients and did not call for immunological evaluation. However, the immunoglobulin screening at admission allowed for an early diagnosis of the immunodeficiency and timely initiation of immunoglobulin substitution, the key prerequisite for a favorable course of the disease.Simple and inexpensive immuno-globulin measurement during the manage-ment of hospitalized children with community-acquired pneumonia may help in early identification of patients with compromised humoral immunity and prevent serious complications.

Evaluation of Antibody Response to Polysaccharide Vaccine and Switched Memory B Cells in Pediatric Patients with Inflammatory Bowel Disease

Background/AimsInflammatory bowel disease (IBD) is a chronic disease of the gastrointestinal tract, whose etiologies are still unknown. This study was performed to evaluate the humoral immune response in terms of B cell functions in selected IBD patients.MethodsEighteen pediatric patients with IBD, including 12 cases of ulcerative colitis (UC) and six with Crohn disease (CD), were enrolled in this study. The pneumococcal vaccine was injected in all patients, and the IgG antibody level to the polysaccharide antigen was measured before and 4 weeks after injection. The B cell switch-recombination process was evaluated.ResultsFive patients with IBD (three CD and two UC) had defects in B cell switching, which was significantly higher than in controls (p=0.05). Ten patients had a specific antibody deficiency and exhibited a higher frequency of bacterial infection than the healthy group. The mean increased level of IgG after vaccination was lower in IBD patients (82.9±32.5 µg/mL vs 219.8±59.0 µg/mL; p=0.001). Among the patients who had an insufficient response, no significant difference in the number of switched memory B-cell was observed.ConclusionsA defect in B lymphocyte switching was observed in pediatric IBD patients, and especially in those patients with CD. Owing to an increased risk of bacterial infections in those patients with antibody production defects, pneumococcal vaccination could be recommended. However, not all patients can benefit from the vaccination, and several may require other prophylactic methods.

Measurement of Pneumococcal Polysaccharide Vaccine Responses for Immunodeficiency Diagnostics: Combined IgG Responses Compared to Serotype Specific IgG Responses

Common variable immunodeficiency (CVID) is a heterogeneous primary immunodeficiency mainly characterized by defective antibody production and markedly reduced serum levels of IgG, IgA and frequently IgM [1]. One hallmark in the diagnosis is a poor response to vaccination [2], which is often gauged by measuring IgG responses to 23-valent pneumococcal polysaccharide (PnPS) vaccine. The majority of childhood vaccination programs now include vaccination against Pneumococcal disease using a 7-, 10or 13valent conjugated Pneumococcal vaccine, that has been shown to provide protection against invasive Pneumococcal disease by the serotypes in these vaccines [3]. However, vaccination using a conjugate Pneumococcal (Pn-C) vaccine may interfere with the diagnostic use of the 23-valent polysaccharide vaccine [4]. Different methods for the quantification of the Pn-PS vaccination response are available and in use by diagnostic laboratories, such as IgG measurement of separate serotypes by luminex [5–7] or ELISA [6, 8], and a commercially available combined Pn-PS IgG measurement by ELISA. We here compare the usefulness of the combined PnPS IgG measurement with specific serotype measurement in a defined cohort of immunodeficiency patients and control patients. Our data show that the ELISA-based combined measurement of IgG Pn-PS responses can mask the presence of immunodeficiency in up to 42 % of patients. We conclude that the luminex-based serotype specific method is superior in detection of Pn-PS vaccination responses and thereby for immunodeficiency diagnostics.

Children diagnosed with common variable immune deficiency show distinct T cell maturation phenotypes when compared with adults (P3333)

Abstract INTRODUCTION: Common variable immune deficiency (CVID) is considered primarily a B cell disorder characterized by low immunoglobulin levels, defective specific antibody production and susceptibility to sinopulmonary infections. Recent studies have implicated T cells in the pathogenesis of CVID. OBJECTIVES: To compare T cell maturation in children and adults with CVID. METHODS: Through PRIMES (Canadian Primary IMmunodeficiency Evaluation Study) registry, we recruited eight children and ten adults with CVID. T cell phenotype was assessed by flow cytometry. Patients were compared to healthy controls (thirteen children and ten adults). Wilcoxon Rank Sum test was used to assess differences in T cell subsets. RESULTS: Total lymphocyte count, CD3, CD4 and CD8 lymphocytes were decreased in children with CVID compared to controls (p=0.0006, p=0.0003, p=0.0003, p=0.03). Percentage and absolute numbers of naïve (p=0.012, p=0.002) and absolute numbers of memory cells (p=0.001) were decreased in children with CVID. However, there were no statistical differences between adults with CVID and healthy controls. DISCUSSION: Our data shows decreased T cell subsets in childhood CVID while levels in adults were normal. Studies assessing temporal trends in T cell subsets are required to determine if these differences in children are due to age-related compensatory mechanisms or if different mechanisms play a role in the pathogenesis of childhood versus adult onset CVID.

Fyn Kinase Is Required for Optimal Humoral Responses

The generation of antigen-specific antibodies and the development of immunological memory require collaboration between B and T cells. T cell-secreted IL-4 is important for B cell survival, isotype switch to IgG1 and IgE, affinity maturation, and the development of germinal centers (GC). Fyn, a member of the Src family tyrosine kinase, is widely expressed in many cell types, including lymphocytes. This kinase is known to interact with both the B cell and T cell receptor (BCR and TCR, respectively). While Fyn deletion does not impair the development of immature T cells and B cells, TCR signaling is altered in mature T cells. The current study demonstrates that Fyn deficient (KO) B cells have impaired IL-4 signaling. Fyn KO mice displayed low basal levels of IgG1, IgE and IgG2c, and delayed antigen-specific IgG1 and IgG2b production, with a dramatic decrease in antigen-specific IgG2c following immunization with a T-dependent antigen. Defects in antibody production correlated with significantly reduced numbers of GC B cells, follicular T helper cells (TFH), and splenic plasma cells (PC). Taken together, our data demonstrate that Fyn kinase is required for optimal humoral responses.

Blood CD4+CD45RO+CXCR5+ T cells are decreased but partially functional in signal transducer and activator of transcription 3 deficiency

The generation of high-affinity antibodies requires the presence of a population of CD4+ T cells (follicular TH [TFH] cells) in the lymph node follicles. These cells differ from TH1, TH2, and TH17 effector cells in that they strongly express activation markers and the chemokine receptor CXCR5 and secrete large amounts of IL-21 and CXCL13. Small numbers of nonactivated CD4+CD45RO+CXCR5+ T cells are also found in the blood. We sought to obtain in vitro a population close to the TFH cells and to study the presence of this cell population among patients with autosomal dominant hyper-IgE syndrome carrying heterozygous signal transducer and activator of transcription 3 (STAT3) mutations that impair the IL-21 signaling required for B-cell differentiation. CD4+CD45RO+CXCR5+ T cells were isolated from blood and activated by CD3/T-cell receptor. We found that CD4+CD45RO+CXCR5+ activated T cells corresponding to circulating bona fide memory TFH cells and that STAT3-deficient patients have abnormally low numbers of "TFH-like" blood T cells. However, STAT3-deficient TFH cells have much the same phenotypic and functional characteristics as TFH cells from healthy control subjects. The ability of STAT3-deficient TFH cells to produce IL-21 on CD28/T-cell receptor activation and to proliferate did not differ from that observed for control TFH cells in vitro. Although the STAT3-deficient TFH cells were also able to help control B cells to produce IgG and IgA, induction of IgG production by naive B cells was impaired. Heterozygous mutations in STAT3 lead to reduced numbers of circulating TFH-like cells, a finding that might account (at least in part) for the observed defect in antibody production.

Syndromic diarrhea/Tricho-hepato-enteric syndrome

Syndromic diarrhea/Tricho-hepato-enteric syndrome (SD/THE) is a rare and severe bowel disorder caused by mutation in SKIV2L or in TTC37, 2 genes encoding subunits of the putative human SKI complex. The estimated prevalence is 1/1,000,000 births and the transmission is autosomal recessive. The classical form is characterized by 5 clinical signs: intractable diarrhea of infancy beginning in the first month of life, usually leading to failure to thrive and requiring parenteral nutrition; facial dysmorphism characterised by prominent forehead and cheeks, broad nasal root and hypertelorism; hair abnormalities described as woolly and easily removable; immune disorders resulting from defective antibody production; intrauterine growth restriction. The aetiology is a defect in TTC37, a TPR containing protein, or in the RNA helicase SKIV2L, both constituting the putative human ski complex. The ski complex is a heterotetrameric cofactor of the cytoplasmic RNA exosome which ensures aberrants mRNAs decay. The diagnosis SD/THE is initially based on clinical findings and confirmed by direct sequencing of TTC37 and SKIV2L. Differential diagnosis with the other causes of intractable diarrhea is easily performed by pathologic investigations. During their clinical course, most of the children require parenteral nutrition and often immunoglobulin supplementation. With time, some of them can be weaned off parenteral nutrition and immunoglobulin supplementation. The prognosis depends on the management and is largely related to the occurrence of parenteral nutrition complications or infections. Even with optimal management, most of the children seem to experience failure to thrive and final short stature. Mild mental retardation is observed in half of the cases. in FrenchLes diarrhées syndromiques ou syndrome tricho-hepato-enterique (SD/THE) sont un syndrome rare et sévère dont l’incidence est estimée à 1 cas pour 1 million de naissances et la transmission autosomique récessive. La forme typique associe 5 signes cliniques: une diarrhée grave rebelle nécessitant dans la majorité des cas une nutrition parentérale du fait de la malnutrition, une dysmorphie avec un front large et bombé, une racine du nez large et un hypertélorisme, des anomalies des cheveux qui sont fragiles, cassants, incoiffables et qualifiés de « laineux », un retard de croissance intra utérine et des anomalies de l’immunité à type de déficit en immunoglobuline ou d’absence de réponse aux antigènes vaccinaux. Des anomalies de deux protéines peuvent être à l’origine du syndrome SD/THE: TTC37, une protéine à motif TPR et SKIV2L, une hélicase à ARN, toutes 2 étant des constituants du complexe SKI humain. Le complexe SKI est un co-facteur de l’exosome cytoplasmique qui assure la dégradation des ARN aberrants ou exogènes. Le diagnostic est d’abord clinique puis confirmé par le séquençage des gènes TTC37 et SKIV2L. Le diagnostic différentiel avec les autres formes de diarrhées intraitables est fait grâce aux analyses anatomopathologiques qui montrent dans les autres formes, des lésions spécifiques. La prise en charge clinique repose sur la nutrition parentérale et la supplémentation en immunoglobuline si nécessaire. Un certain nombre d’enfants peuvent être sevrés de la nutrition parentérale et des supplémentations en immunoglobulines. En cas d’atteinte hépatique, celle-ci peut être sévère et conduire au décès. Même avec une prise en charge optimale, les enfants présentent une petite taille et, dans la moitié des cas, un retard mental modéré.Disease name/synonyms – Syndromic diarrhea – Phenotypic diarrhea – Tricho-hepato-enteric syndrome – Intractable diarrhea of infancy with facial dysmorphism – Trichorrhexis nodosa and cirrhosis – Neonatal hemochromatosis phenotype with intractable diarrhea and hair abnormalities – Intractable infant diarrhea associated with phenotypic abnormalities and immune deficiency- Syndromatic diarrhea. [ORPHA84064 MIM 222470 and MIM614602]. Possibly chronic diarrhea and skin hyperpigmentation.

Food allergy in children with hypogammaglobulinemia

IntroductionAntibody production defects may predispose children to inflammatory pathologies and therefore we hypothesized that this group of immune deficiencies may be associated with food allergy. Objective of the studyTo better characterize the interrelated pathomechanisms of food allergy coexisting with hypogammaglobulinemia in children and to define the relationship between clinical manifestation of antibody production defects and food allergy. Material and methodsTwenty-three children aged from 8 to 88 months regularly followed-up in the pediatric pneumonology, allergology and immunology clinic due to hypogammaglobulinemia concerning one or more major immunoglobulin isotypes were retrospectively reviewed in terms of incidence and manifestation of concomitant food allergy. Information regarding the patient's history of allergic diseases and laboratory data concerning serum levels of immunoglobulins, including total IgE, were obtained from chart review. ResultsClinical symptoms of food allergy were identified in 17 of 23 (74%) children studied. The mean age of onset of clinical symptoms was 2.7 months. Eczema was the most frequent manifestation present in 16 children, diarrheas and abdominal cramps were noted equally in 3 children, gastroesophageal reflux disease was diagnosed in 2 children as well as vomiting was observed in 2 children. Atopy was revealed in 8 of 17 children (47%) with food allergy. ConclusionsFood allergy is a common health problem coexisting with antibody production defects in infants and young children. Clinical symptoms correlate better with low immunoglobulin levels than with serum IgE, that is not a suitable diagnostic criterion for allergic disease in patients with hypogammaglobulinemia.

Defective regulatory T cells function and spontaneous colitis induced by protein phosphatase 4-deficiency (120.14)

Abstract Protein phosphatase 4 (PP4) is essential during early T cells development. To assess the function of PP4 in peripheral T cells, we generated conditional PP4 knockout mice with CD4-cre transgene (CD4cre-PP4f/f). In these mice a partial block of thymocyte development was manifested as a ~40-60% reduction of peripheral T cells. Further studies showed that PP4 deletion resulted in poor T cell proliferation, inefficient Treg polarization, decreased Treg cell number and reduced Treg suppression activity. In vivo, CD4cre-PP4f/f mice exhibited defective T-dependent antibody production. More interestingly, by 5-month old ~50% of the CD4cre-PP4f/f mice developed spontaneous colitis with wasting syndrome, and showed increased percentages of IFNgamma+, IL-6+, or IL-17A+-producing cells in intra-epithelial lymphocytes and lamina propria lymphocytes. When investigating the pathogenesis of colitis, we found that transferring PP4-deficient CD4+CD45RBhigh cells failed to induce colitis in RAG-/- recipients, whereas antibiotics treatment could reverse the wasting syndrome. Combined with the defects in Treg and antibody production, these results are consistent with the possibility that PP4 deficiency reduced the efficiency of mucosal immunity against commensal bacteria, causing uncontrolled gut inflammation that eventually develop into colitis. The spontaneous colitis in CD4cre-PP4f/f mice may thus serve as an unique model for studying the pathogenesis of human inflammatory bowel disease.

PI3 Kinase δ Is a Key Regulator of Synoviocyte Function in Rheumatoid Arthritis

Class I phosphoinositide 3 kinase (PI3K) δ is a promising therapeutic target for rheumatoid arthritis (RA) because of its contribution to leukocyte biology. However, its contribution in fibroblasts has not been studied as a mechanism that contributes to efficacy. We investigated the expression and function of PI3Kδ in synovium and cultured fibroblast-like synoviocytes (FLS). Immunohistochemistry demonstrated that PI3Kδ is highly expressed in RA synovium, especially in the synovial lining. Using quantitative PCR and Western blot analysis, we found that PI3Kδ mRNA and protein expression is higher in RA than in osteoarthritis (OA) synovium. PI3Kδ was also expressed in cultured FLS, along with PI3Kα and PI3Kβ, whereas PI3Kγ was not detectable. PI3Kδ mRNA expression was selectively induced by inflammatory cytokines tumor necrosis factor (TNF) and interleukin-1 (IL-1) but not by growth factors platelet-derived growth factor (PDGF) and transforming growth factor β (TGFβ). The use of inhibitors that block individual PI3K isoforms, including the novel selective PI3Kδ inhibitor INK007, showed that PI3Kδ is required for PDGF- and TNF-induced Akt activation. PI3Kδ inhibition also diminished PDGF-mediated synoviocyte growth and sensitized cells to H(2)O(2)-induced apoptosis. These data are the first documentation of increased PI3Kδ expression in both RA synovium and cultured synoviocytes. Furthermore, these are the first data demonstrating that PI3Kδ is a major regulator of PDGF-mediated fibroblast growth and survival via Akt. Thus, targeting PI3Kδ in RA could modulate synoviocyte function via anti-inflammatory and disease-altering mechanisms.

Subcutaneous immunoglobulin therapy: a new option for patients with primary immunodeficiency diseases.

Since the 1950s, replacement of immunoglobulin G using human immunoglobulin has been the standard treatment for primary immunodeficiency diseases with defects in antibody production. These patients suffer from recurrent and severe infections, which cause lung damage and shorten their life span. Immunoglobulins given intravenously (IVIG) every 3–4 weeks are effective in preventing serious bacterial infections and improving the quality of life for treated patients. Administration of immunoglobulin subcutaneously (SCIG) is equally effective in preventing infections and has a lower incidence of serious adverse effects compared to IVIG. The tolerability and acceptability of SCIG has been demonstrated in numerous studies showing improvements in quality of life and a preference for subcutaneous immunoglobulin therapy in patients with antibody deficiencies.

New frontiers in primary immunodeficiency disorders: immunology and beyond….

Primary immunodeficiencies (PIDs) include more than 130 different disorders affecting the development and function of the immune system [1, 2]. PIDs are generally monogenic disorders with a Mendelian inheritance, although a more complex polygenic origin has been described in some cases. PIDs are characterized by a variable clinical spectrum. As for other genetic diseases, phenotypic diversity is often caused by disease penetrance and interactions between genetic and environmental factors. PIDs are rare and have an overall prevalence of approximately 1:10,000 live births, with the exception of IgA deficiency (IgAD). However, a much higher rate is observed among populations with high consanguinity rates or genetically isolated. PIDs are classified according to the component of the immune system that is mostly engaged. Defects in adaptive immune responses include antibody deficiency syndromes and combined immunodeficiencies (CIDs). Conversely, impairment of innate immunity comprises disorders of several cells and molecules involved in the first defense against pathogen (i.e., phagocytes, Toll-like receptors, complement, NK cell). All of these forms are characterized by increased susceptibility to recurrent infections, severe infections, and sometime distinctive susceptibility to various types of pathogens depending on the nature of the immune defect. In addition, there are some forms of PIDs presenting mainly with a phenotype of immune dysregulation rather than immunodeficiency, and there are also syndromes with complex phenotype in which immunodeficiency is only one of multiple components of the disease spectrum. PIDs affecting the B and T cell compartment are traditionally the ‘‘classic’’ forms of inherited immune deficit widely described and usually recognized also by general practitioners. Defective antibody production causes increased susceptibility, primarily to bacterial infections with involvement of the upper and lower respiratory tract (otitis, sinusitis, and pneumonia), although recurrent viral infections are also common as well as infections caused by parasites (i.e., Giardia species) [2, 3, 4]. Primary antibody deficiencies (PAD) are the largest group of inherited disorders of the immune system [5] and comprise a variety of defects that interfere with B cell development, maturation, and/or function. They are mainly characterized by a marked reduction or absence of serum immunoglobulins (Ig) due to disturbed B cell differentiation. X-linked agammaglobulinemia (XLA) is a well-described condition affecting males and characterized by mutation of the X-linked Bruton’s tyrosine kinase (BTK) gene [6, 7], named after Dr. Bruton, who described the first agammaglobulinemia patient in 1952 [8]. BTK, a transduction molecule of both pre-B cell-receptor (pre-BCR) and BCR, is essential for B cell differentiation in bone marrow. Besides XLA, many other gene defects were found as responsible of PAD and most of them have only been identified over the past 6 years. Moreover, the discovery of new PAD has contributed also to improve the clinical care of affected patients. The review by van der Burg et al. E. Gambineri (&) Department of Sciences for Woman and Child’s Health, ‘‘Anna Meyer’’ Children’s Hospital, Haematology-Oncology Department, BMT Unit, University of Florence, Viale Gaetano Pieraccini, 24, 50139 Florence, Italy e-mail: eleonora.gambineri@unifi.it Cell. Mol. Life Sci. (2012) 69:1–5 DOI 10.1007/s00018-011-0833-0 Cellular and Molecular Life Sciences

Abstract 805: mTORC protein levels affect class switch recombination, somatic hypermutation, and antibody production

Abstract Mammalian target of rapamycin (mTOR) regulates cell growth, cell cycle, and survival through two main complexes, mTORC1 and mTORC2. In our previous studies, striking decreases in both size and number of B cells were seen in mice with constitutive reductions in protein levels of both mTOR complexes. In addition, there were alterations in B cell differentiation with partial blocks in B cell development in the bone marrow. In our current studies, we have focused on their defect in antibody production. When challenged with either NP-CGG (T-dependent antigen) or NP-LPS (T-independent antigens), reduced IgG antibody titers to NP antigens were seen in mice with constitutive reductions in mTOR protein levels, despite equivalent levels of total antibody production; high affinity antibody production was also less. The numbers of germinal centers were reduced in the spleens of the mTORC1/2-compromised mice compared to their wild-type littermates. Fewer B cells from the mTORC1/2-compromised mice were able to undergo class switching from IgM to IgG. In addition, germinal center B cells from these mice exhibited reductions in somatic hypermutation rates of their immunoglobulin loci. Studies are currently underway to evaluate the ability of these mice to respond to an in vivo challenge of live bacteria. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 805. doi:10.1158/1538-7445.AM2011-805

Giardiasis in Common Variable Immunodeficiency (CVID)

Purpose: Patients with common variable immunodeficiency (CVID) are prone to bacterial infections because of defective antibody production and decreased serum immunoglobulins [1]. In patients with CVID, giardiasis may cause enterocyte damage, subtotal villous atrophy and development of a nodular mucosa [2]. Presentation: 60-year-old male with past medical history of diabetes and common variable immune deficiency was referred for the evaluation of chronic intermittent abdominal pain, bloating, intermittent diarrhea and constipation. He denied any appetite or weight changes.Physical examination revealed a moderately built male with normal vitals signs and a negative abdominal examination. Diagnostic Evaluation: Stool studies were negative for occult blood, ova and parasites and cultures showed normal enteric flora. Blood work and imaging studies including a CT abdomen and small bowel follow through were normal. An EGD showed a nodular appearing mucosa in the duodenum (Figure A). Histopathology of the stomach was negative for H. pylori but the duodenal biopsies revealed acute cryptitis with crypt abscesses (Figure B) and abundant giardia trophozoites (Figure C). The patient was started on metronidazole, 500 milligrams thrice a day for 10 days with resolution of his symptoms. Discussion: Giardiasis is caused by a flagellate parasite. Stool antigen testing by Enzyme linked immune sorbant assay (ELISA) and Immunofluorescent assay (IFA) has high sensitivity and specificity. Endoscopic duodenal sampling is the most sensitive test to detect giardiasis while rarely necessary. Treatment of giardiasis in patients with CVID may be difficult because of frequent relapses and chronicity. Metronidazole is the drug of choice but resistant cases have been treated with tinidazole, ornidazole and quinacrine [3].Figure: [685]

Echocardiographic abnormalities and their correlation with bronchiectasis score in primary antibody deficiencies

Primary antibody deficiencies are characterized by defective antibody production and recurrent infections. Patients usually present with recurrent respiratory tract infections with consequent chronic pulmonary damage and bronchiectasis, which could potentially influence cardiac function. Our aim was to assess noninvasively the cardiac complications due to pulmonary disease in patients with primary antibody deficiency. A cross-sectional series of patients with primary antibody deficiency syndromes from our referral immunology center were recruited. Individuals undergoing high-resolution computed tomography (HRCT) and transthoracic echocardiography were reviewed. Thirty primary immunodeficient patients aged 5-55 years of age (21 males and 9 females) were enrolled in this study. Half of the patients (50%) were found to have bronchiectasis in HRCT imaging. In echocardiographic examination, 20 patients (67%) had at least one abnormality; among which pulmonary hypertension was the most common (33%). Patients with bronchiectasis had higher pulmonary artery pressures and HRCT bronchiectasis score was strongly correlated with pulmonary artery pressure (regression R = 0.59, P value = 0.001). Echocardiographic evaluation of right ventricular function and noninvasive estimation of pulmonary artery pressure could have an important diagnostic role in the follow-up and therapeutic management of patients with primary immune deficiency.