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Chronic rhinosinusitis (CRS) is estimated to affect over 35 million people. However, not all patients with the diagnosis respond to standard medical and surgical treatments. Although there are a variety of reasons a patient may be refractory to therapy, one possible etiology is the presence of an underlying immunodeficiency. This review will focus on the description, recognition, and treatment of several antibody deficiencies associated with CRS, including common variable immunodeficiency (CVID), selective IgA deficiency, IgG subclass deficiency, and specific antibody deficiency (SAD). The diagnosis of antibody deficiency in patients with CRS is important because of the large clinical implications it can have on sinus disease management. CVID is treated with immunoglobulin replacement, whereas SAD may be managed symptomatically and sometimes with prophylactic antibiotics and/or immunoglobulin replacement.

Background Recurrent acute epiglottitis is uncommon in adults. In the medical literature, very little is known about the immune status of this population. Objective To evaluate the immune system of a group of four adult patients with recurrent acute epiglottitis, in what represents the largest series ever reported. Methods The clinical course of these episodes was carefully evaluated and a basic immune deficiency work-up was carried out for each patient. Results All four patients displayed clinical and laboratory evidence of impaired humoral immunity. One patient was splenectomized. Another patient had a below normal immunoglobulin G level. At the time of their first evaluation, none of our patients had specific antibodies against Haemophilus influenzae and one had a subnormal Streptococcus pneumoniae immunoglobulin G level for a majority of serotypes. After specific vaccination, two patients had persistent abnormalities in their response to one or more polysaccharides or conjugate-polysaccharide antigens. In the other two, the transient abnormalities were corrected by immunization. Conclusions When recurrent acute epiglottitis occurs in adults, it is important to investigate the immune system because a quantitative or a specific antibody deficiency could be found. It also follows that these patients will be successfully treated either by immunization or antibody replacement.

Coincidence of autoimmune diseases such as immune thrombocytopenic purpura (ITP) with immunodeficiencies has been reported previously in patients who suffered from primary antibody deficiency (PAD). But there is no original study on immunological profiles of ITP patients to find out their probable immune deficiency. In this case-control study, ITP patients’ humoral immunity was investigated for diagnosis of PAD in comparison with normal population. To evaluate the humoral immune system against polysaccharide antigens, patients’ serum immunoglobulin levels were measured and a 23-valent pneumococcal capsular polysaccharide vaccine (PPV23) was administrated to evaluate the antibody response to vaccination. In this study, 14 out of 36 patients (39%) were diagnosed with antibody mediated immune deficiency including 2 patients (5.5%) with immunoglobulin class deficiency and 4 (11%) with IgG subclass deficiency. The remaining patients suffered from specific antibody deficiency. The most frequent deficiency in ITP patients was specific antibody deficiency. Therefore, immunological survey on ITP patients may be important especially for those who have undergone splenectomy.

Background Several studies have shown a high prevalence of immunoglobulin deficiencies in patients with chronic rhinosinusitis (CRS). Objective We sought to perform a systematic review and meta-analysis to estimate this prevalence more precisely and to identify patients who need substitution treatment. Methods All case series published after 1990 describing patients with CRS, which was defined as symptomatic rhinosinusitis for more than 12 weeks and documented immunoglobulin deficiencies (including deficiencies of IgG with subclasses, IgA, and IgM; specific antibody deficiencies; and potential common variable immunodeficiency), were retrieved. A meta-analysis of the proportion of any combination of common variable immunodeficiency, IgG deficiency, IgA deficiency, and IgM deficiency in patients with CRS was performed by using logit transformation of the prevalence. Recurrent CRS was defined as rhinosinusitis not controlled by appropriate conservative management for 4 months, and difficult-to-treat CRS was defined as noncontrollable rhinosinusitis despite successful sinus surgery and appropriate conservative management for at least 1 year. Results The meta-analysis revealed a prevalence of pooled IgG, IgA, and IgM deficiencies in 13% of patients with recurrent CRS and 23% of patients with difficult-to-treat CRS. The prevalence of IgG subclass deficiency (5% to 50%) and specific antibody deficiency (8% to 34%) was increased in patients with CRS, as was the prevalence of respiratory allergies in patients with recurrent CRS (31% to 72%). Conclusion Immunoglobulin deficiency is a frequent condition in patients with CRS. An even higher prevalence of atopy was observed in patients with recurrent CRS. Therefore immunoglobulin titers and accurate allergy diagnostic workups are strongly recommended in these patients to provide specific treatments for symptom alleviation. However, there is a need for larger prospective studies addressing the effect of specific therapeutic interventions for CRS.

Clinical observations in patients with specific antibody deficiency treated for periods of time with IgG infusion have suggested that IgG may have a positive immunoregulatory effect on the production of specific antibodies against pneumococcal polysaccharides. We developed an in vitro model to test the effect of an IgIV preparation on the antibody production in response to a pneumococcal polysaccharide serotype and on the antibody and cytokine production in response to both a protein antigen and a pneumococcal polysaccharide antigen. We studied 37 consecutive patients referred to our clinics for evaluation of their recurrent respiratory infections. Subjects were divided into two groups: 22 patients without SAD and 15 patients with SAD. PBMCs were left unstimulated or were stimulated with tetanus toxoid or pneumococcal polysaccharide serotype 19, in the presence of human albumin or IgIV. IgG anti-Pn-19 antibody, IL-4 and IFN-γ concentrations in culture supernatants were determined by ELISA. An increase in IgG anti-Pn-19 antibodies, associated with an increase in IFN-γ and a decrease in IL-4 production was observed in cultures stimulated with pneumococcal polysaccharide in the presence of IgIV when patients were analyzed together. The enhancing effect of IgIV was more significant for both IgG anti-Pn19 antibodies and IFN-γ in patients without SAD. In contrast, IgIV caused a significant decrease in IL-4 secretion in patients with SAD, which was associated with an increase in IgG anti-Pn19 antibodies in 3 of 7 of these patients. These results suggest that IgIV has some immunomodulatory effect on the in vitro production of IgG anti-Pn19 antibodies and cytokine production in cell cultures stimulated with Pn-19 antigen and that this modulation may be associated with a Th1/Th2 regulatory mechanism. Further studies at a cellular and molecular level are in progress to examine if the differences in the in vitro modulatory response to IgIV in these two groups of patients may point to a functional defect in patients with SAD.

Primary immunodeficiency is rare but should be considered in patients who present to the otolaryngologist with recurrent, severe, or treatment refractory infections.Recent literature and consensus statements on immunodeficiency were reviewed for clinically important information of relevance to otolaryngologists.The most common and most relevant immunodeficiencies are humoral deficiencies with inadequate antibody production or an impairment in the production of specific antibody after antigen exposure. For otolaryngologists the most important immunodeficiencies include immunoglobulin A (IgA) deficiency, common variable immunodeficiency (CVID), and specific antibody deficiency. Simple screening tests can be used by the otolaryngologist to exclude the most common immunodeficiencies. The general treatment approach to patients with these immunodeficiencies includes airway hygiene, early and aggressive treatment of infections, immunization, and antibody replacement therapy.By virtue of their scope of practice, otolaryngologists are in a position to recognize and initiate the diagnostic workup of patients with immunodeficiency. Patients with a diagnosed primary immunodeficiency are best managed in a multidisciplinary manner with close cooperation among the otolaryngologist, immunologist, and other specialists that are involved in treating these multisystem diseases.

Patients with antibody deficiency rely on immunoglobulin products for protection against many vaccine-preventable diseases. We measured antibody titers against Bordetella pertussis and Neisseria meningitidis in patients receiving immunoglobulin (IG) therapy to determine if they have any protection against infections from these organisms. In an unblinded, prospective assessment we measured antibody titers against B. pertussis filamentous hemagglutinin (FHA) and pertussis toxin (PT) antigens and N. meningitidis serogroups A, C, W-135, and Y in patients receiving immunoglobulin therapy for primary immune deficiency (PI). We measured steady state levels in patients receiving subcutaneous immunoglobulin therapy while in patients receiving intravenous immunoglobulin therapy we measured titers immediately before and after infusion to more clearly define the contribution of the infused product. Thirty subjects, 17 females and 13 males, participated in the study, 22 were receiving intravenous IG products and 8 were receiving subcutaneous IG products. Diagnoses included common variable immunodeficiency in 12, combined immunodeficiency in 6, specific antibody deficiency in 6, X-linked agammaglobulinemia in 4 and ataxia telangiectasia and hyper-IgE syndrome in one each. All subjects had detectable IgG antibodies against the pertussis antigens measured and most had antibody to the meningococcus serotypes measured. However, only 26.6 % had protective levels (>= 2 mcg/mL) against serogroup C at trough or steady state. Patients receiving immunoglobulin therapy have antibodies against B. pertussis and most of them have antibodies against the four measured serogroups of N. meningitidis. There is significant variability in the levels of antibody between patients and the low titers against group C may suggest a role for active immunization in those who may respond to conjugated polysaccharide vaccine administration.

To compare the efficacy of immunoglobulin replacement therapy given intravenously versus subcutaneously to prevent infections in patients with primary antibody deficiency syndromes, an international, multicenter, open label, crossover study was designed. Forty patients were randomized to receive either subcutaneous or intravenous immunoglobulin replacement therapy for 1 year. In the second year, patients were switched to the alternative treatment, enabling patients to act as their own controls. Equivalent doses were given by both routes. Ethical approval was obtained from the review boards of the hospitals in which the patients were seen and written consent obtained from each patient. Patients with a primary antibody deficiency syndrome, either common variable immunodeficiency or IgG subclass deficiency or specific antibody deficiency, who required immunoglobulin replacement therapy were included in the study. Patients were excluded if they had significant thrombocytopenia (defined as platelets less than 50 × 109/liter), had high levels of anti-IgA antibodies (defined as greater than 1:8192), or had severe adverse reactions to a blood product within the last 2 years. The primary end point was the number of infections and their severity (moderate and major) during the two treatment periods. Secondary end points were adverse reactions, length of infections, days lost from school or work due to infections, and acceptability of treatment regimens to the patients. Based on the assumption that it was difficult to prove equivalence of therapies statistically in crossover studies, an arbitrary number of 40 patients was selected on the basis that this might be achievable in 2 years. There are no significant differences in efficacy or adverse reaction rates between immunoglobulin replacement therapy given subcutaneously or intravenously.

Background: A deficient antibody response to polysaccharide antigens is determined by measuring the response to the 23-valent pneumococcal polysaccharide vaccine. However, the diagnosis of this specific antibody deficiency is hampered by the lack of sufficient data and standardized testing of the response to pneumococcal polysaccharides. Methods: All patients evaluated in our allergy/immunology clinic for recurrent respiratory infections between 1995 and 1997 without immunoglobulin, IgG subclass, or other known primary or secondary immunodeficiency were included in this analysis. IgG antipneumococcal serotypes 1, 3, 4, 6B, 9V, 14, 18C, 19F, and 23F were determined by a modified ELISA protocol. An adequate IgG antibody response to an individual serotype was arbitrarily defined as a postimmunization antibody titer of 1.3 μg/ml or greater or at least four times the baseline value. Results: A total of 113 patients fulfilling the criteria for inclusion in this analysis were divided into five age groups. The geometric means for preimmunization and postimmunization pneumococcal antibody titers for all serotypes increased with age. For postimmunization antibody concentrations, there was a sharp increase in the specific antibody concentrations in adults in comparison with all pediatric age groups ranging in age from 7 months to 16 years. Similarly, the number of serotypes to which there was an adequate response also increased with age. Conclusion: We conclude that the definition of what constitutes an adequate response to pneumococcal immunization needs further definition. It is clear, however, that age has an important influence on the intensity of the response to most pneumococcal polysaccharides. Correlation studies between antibody concentrations in different IgG subclasses, functional studies, and protection studies against mucosal and invasive pneumococcal infections are in progress, and these should contribute to a refined definition of a normal response. The availability of a standardized method for the measurement of IgG antibodies against relevant pneumococcal serotypes is an important step toward this goal. (J Allergy Clin Immunol 1998;102:215-21.)

Janssen et al in this journal published their paper “Measurement of pneumococcal polysaccharide vaccine responses for immunodeficiency diagnostics: combined IgG responses compared to serotype specific IgG responses”. It is important to note that the message of this study is the observation that measuring antibodies against a mixture of all 23 pneumococcal serotype polysaccharides by ELISA does not reliably identify patients with a deficient response to pneumococcal polysaccharides. This holds true for patients with CVID, Specific Antibody Deficiency (SAD) or any other immunodeficiency affecting antibody production. Therefore, this study confirms a finding that is well established and beyond question; the only way to properly assess the ability of producing IgG anti-pneumococcal antibodies is to measure antibodies to each serotype individually. This is particularly important in the diagnosis of SAD since this deficiency is defined as an abnormal response to pure pneumococcal polysacchrides, as in the 23-valent poneumococcal vaccine [1]. Now that most young patients are already vaccinated with a pneumococcal conjugate vaccine and may have developed antibodies to serotypes present in these vaccines, the global ELISA test would not be able to identify the lack of response to serotypes that are only in the 23-valent polysaccharide and not in the conjugate vaccines. The study by Janssen et al does lend further clarification about the value of the Luminex method for the diagnosis of SAD. The Luminex method is now used by most commercial laboratories in the USA because it offers significant logistic advantages over the well-standardized but more cumbersome WHO ELISA method. Luminex allows the simultaneous quantitation of multiple serotype-specific antibodies. Both the third generation WHO ELISA and Luminex based tests offered in the USA incorporate double absorption of samples with cell wall polysaccharide (CPS) and serotype 22F. The WHO ELISA test results have been shown to correlate closely with opsonophagocytosis (OPA) measurements [2, 3]. Although the Luminex method has been approved for the measurement of specific anti-pneumococcal serotype IgG antibodies, the correlation of this test with the standard ELISA test is poor and its use as s a diagnostic tool for SAD still needs further study. Recent studies designed to validate the Luminex assay for anti-pneumococcal IgG antibodies have shown different degrees of variability when compared to the ELISA method [4]. Results obtained in a recent comprehensive com

Introduction Classification of immunodeficiency Clinical features of immunodeficiency Investigation of immunodeficiency Laboratory investigation Major B-lymphocyte disorders Rare antibody deficiency syndromes X-linked agammaglobulinaemia (Bruton’s disease) Common variable immunodeficiency (CVID) CVID 2: complications and treatment Selective IgA deficiency IgG subclass deficiency Specific antibody deficiency with normal serum immunoglobulins...

Trabalho final de mestrado integrado em Medicina área cientifica de Imunoalergologia, apresentado á Faculdade de Medicina da Universidade de Coimbra Introdução - A deficiência seletiva em IgA (DIgA) é a mais comum das imunodeficiências primárias em vários grupos étnicos. A sua prevalência em caucasianos é de aproximadamente 1 em 600. DIgA é causada por um defeito na diferenciação terminal linfocitária que leva a diminuição da produção da IgA sérica e mucosa. Apesar da maioria dos indivíduos serem assintomáticos os que apresentam sintomas têm predominantemente infecções pulmonares e gastrointestinais, que são mais severas se associadas a défices de anticorpos específicos ou de IgG2/IgG4, podendo ser acompanhada também por atopia. A DIgA primária parece ser mais prevalente que a secundária. Objetivos - Revisão da literatura sobre deficiência seletiva de IgA criando-se um algoritmo de orientação geral nos indivíduos suspeitos. Métodos - Revisão bibliográfica dos últimos 20 anos usando PubMed; pesquisa direta; Pediatrics Publications; Liliacs. Conclusão - DIgA é a imunodeficiência mais comum com uma prevalência média de 1:600 e deve ser estudada nas suas vertentes clínicas laboratoriais e terapêuticas, assim como as possíveis complicações no sentido de determinar um diagnóstico correto e definir um prognóstico. Introduction - IgA deficiency is the most common primary immunoglobulin deficiency in many ethnic populations. The prevalence in Caucasians is approximately one in 600. Primary IgA deficiency is caused by a defect of terminal lymphocyte differentiation, which leads to underproduction of serum and mucosal IgA. Despite most individuals being asymptomatic, those with symptoms of immunodeficiency have predominant sinopulmonary and gastrointestinal infections, which are more severe there is associated IgG2/IgG4 ou IgG4 subclass or specific antibody deficiency. There is a possible atopy in IgA deficiency. Selective IgA deficiency appears to be the most prevalent comparing to secondary. Objectives - Revise the literature about the subject with selective IgA deficiency creating an algorithm to general orientation in suspect individuals Methods - Bibliografic review of the last twenty years about the subject using PubMed; direct research; Pediatrics Publications; Liliacs Conclusion - IgA deficiency is the most frequent primary immunodeficiency, with the average prevalence of 1:600 and must be studied in its clinical, laboratorial and therapeutic aspects of the toal and partial immunodeficiency must be known, so as the complications and laboratory techniques for determine accurate diagnosis and prognostic.

Yellow nail syndrome (YNS) is a rare disorder of unknown aetiology that is characterized by yellow nails associated with lymphoedema and chronic respiratory manifestations. There are no detailed immunological studies in YNS. In this study, we present first extensive immunological analysis of both adaptive and innate immunity in two patients with YNS. One patient has common variable immunodeficiency, whereas second patient has specific antibody deficiency syndrome. Severe lymphopaenia, a striking deficiency of naïve CD4+ and CD8+ T cells and total B cells, and increased transitional B cells were observed. T cell proliferative response to mitogens and antigens was significantly reduced in both patients. Both patients failed to make specific antibody response to pneumococci. Complement, natural killer cell activity and neutrophil oxidative burst were normal. Immunoglobulin administration resulted in decreased frequency and severity of infections, and an impressive effect was observed on lymphoedema and on the recurrence of pleural effusion. Our data show that YNS is associated with both T and B cell defects. Furthermore, Immunoglobulin may be beneficial in clinical manifestations of lymphoedema.

Background: Selective IgA deficiency (SIGAD) is the most common primary antibody deficiency, characterized by significant decreased serum levels of IgA in the presence of normal IgG and IgM. Despite several investigations into the nature of the disease, the exact pathophysiology of SIGAD is still unknown. Methods: In this study, switched memory B cells (CD19+/CD27+/IgD– cell population) of 28 patients with SIGAD and 28 matched healthy controls were investigated using flow cytometry. Results: The percentage of switched memory B cells in all healthy controls was more than 0.4%. In SIGAD patients, who were classified as group I, the percentage of switched memory B cells was less than 0.4% (0.34 ± 0.06) in 7 patients (25%). The remaining 21 patients were designated as group II (1.74 ± 0.12%). The mean concentration of IgG in group I was significantly lower than in group II (1,014 ± 278 vs. 1,388 ± 406 mg/dl, p = 0.028). Comparison of clinical features between the 2 groups revealed that episodes of pneumonia during the course of disease were significantly higher in group I than in group II (p = 0.002). Autoimmune diseases in group I (57.1%) were also significantly higher (p = 0.01) than in group II (23.8%). The prevalence of bronchiectasis was 57% in group I, while only 1 patient (4.7%) in group II developed bronchiectasis (p = 0.006). Specific antibody deficiency in group I was documented in 5 patients and in group II in 4 patients (p = 0.01). Conclusions: The classification of SIGAD patients by assessment of switched memory B cells could help physicians with the clinical prognosis for these patients, whereas the patients with reduced switched memory B cells are prone to severe phenotypes.

Introduction Complement deficiencies (CDs) are classified as primary immunodeficiency disorders (PIDs) because diminished opsonization or the inability to form the membrane attack complex increases the susceptibility to pyogenic bacterial infections (1). Moreover, diverse autoimmune manifestations occur that vary with the particular CD (1–3). Complement C2 deficiency (C2D; MIM217000) is classically associated with early-onset invasive pneumococcal infections and systemic lupus erythematosus (SLE) or SLE-like manifestations, which typically present in early or middle adulthood (3,4). Due to its low prevalence ( 1:20,000) (4) and variable clinical manifestations, publications on the treatment of C2D are scarce. In this case report, we describe a C2D patient with the earliest onset of SLE published, to our best knowledge, thus far. We report on rare complications such as immune complex–mediated leukocytoclastic vasculitis (LCV), destructive follicular bronchiolitis (DFB) with polyclonal B cell proliferation, and disturbed humoral immune responses, including dysgammaglobulinemia and specific antibody deficiency, therefore defining a novel phenotype. Providing a detailed histologic, immunologic, and genetic workup, we discuss the pathophysiology of C2D as a complex disorder at the interface between innate and adaptive humoral immunity. Finally, we describe, for the first time, the effective treatment with rituximab (RTX), implicating B cell depletion as a therapeutic strategy for the autoimmune manifestations of the PID.

Summary The posters presented at the 6th International Immunoglobulin Symposium covered a wide range of fields and included both basic science and clinical research. From the abstracts accepted for poster presentation, 12 abstracts were selected for oral presentations in three parallel sessions on immunodeficiencies, autoimmunity and basic research. The immunodeficiency presentations dealt with novel, rare class-switch recombination (CSR) deficiencies, attenuation of adverse events following IVIg treatment, association of immunoglobulin (Ig)G trough levels and protection against acute infection in patients with X-linked agammaglobulinaemia (XLA) and common variable immunodeficiency (CVID), and the reduction of class-switched memory B cells in patients with specific antibody deficiency (SAD). The impact of intravenous immunoglobulin on fetal alloimmune thrombocytopenia, pregnancy and postpartum-related relapses in multiple sclerosis and refractory myositis, as well as experiences with subcutaneous immunoglobulin in patients with multi-focal motor neuropathy, were the topics presented in the autoimmunity session. The interaction of dendritic cell (DC)-SIGN and α2,6-sialylated IgG Fc and its impact on human DCs, the enrichment of sialylated IgG in plasma-derived IgG, as wells as prion surveillance and monitoring of anti-measles titres in immunoglobulin products, were covered in the basic science session. In summary, the presentations illustrated the breadth of immunoglobulin therapy usage and highlighted the progress that is being made in diverse areas of basic and clinical research, extending our understanding of the mechanisms of immunoglobulin action and contributing to improved patient care.

The NFkB signaling pathway is a master regulator of the immune response. Recently, dominant mutations in NFKB2 have shown to cause antibody deficiency with adrenal insufficiency. We investigated two families with antibody deficiency and autoinflammatory features, with onset in teenage years and early adulthood (Fig. 1 and Table 1). In family 1, all patients available to study presented with respiratory tract infections and B cell dysfunction marked by hypogammaglobulinemia, poor antibody response to vaccines, or low switched memory B cell counts. Several experienced recurrent episodes of aphthous mucositis in upper gastrointestinal and genital area, sometimes accompanied by abdominal pain, monoarthritis, or fever with elevated inflammatory markers (peripheral blood leukocytes >10x106 cells/ml, C reactive protein >100 mg/L). A lesional biopsy revealed lymphocytic small cell vasculitis reminiscent of Behcet's disease. In family 2, all patients presented with respiratory tract infections, hypogammaglobulinemia, and poor vaccine responses. Based on the pedigrees, we assumed autosomal dominant inheritance. For family 1, we performed genotyping and linkage analysis coupled with whole genome sequencing to pinpoint the causative variant. Linkage analysis showed a 15.4 Mb haplotype on chr4 segregating with the phenotype in all affected individuals. When focusing our search on novel, heterozygous variants negatively affecting conserved residues, we identified only one variant in this genomic location, localizing to NFKB1 gene (p.H67R). In family 2, we exome sequenced one affected individual and filtered the data for novel heterozygous variants negatively affecting conserved residues. This resulted in 17 variants, out of which the I553M NFKB1 variant was considered the best candidate. Several functional analyses showed that the mutations had a negative impact on NFKB1 function. The H67R variant increased NFKB1 affinity to NEMO and delayed protein entry to nucleus, when assessed by affinity purification mass spectrometry and immunofluorescence microscopy. The mutation also decreased NFKB1 transcriptional activity, when expressed together with an NFkB-responsive luciferase reporter, and showed a neomorphic DNA binding pattern on chromatin immunoprecipitation-sequencing. Furthermore, the cell growth was hampered when the mutant NFKB1 was overexpressed in cultured HEK293 cells. The I553M showed a similar negative effect on cultured cell proliferation. Furthermore, the I553M variant negatively affected serine S907 and S893 phosphorylation, leading to defective posttranslational processing of the full-length NFKB1 upon TNF stimulation. To conclude, we show that hypogammaglobulinemia and Behcet's disease-like autoinflammatory syndrome can be caused by mutations in NFKB1. This suggests that a subset of Behcet's disease cases may be of monogenic origin, and highlights the role of NFkB complex in B cell maturation and innate immune regulation. Table 1. Patient characteristics Patient 1 2 3 4 5 6 7 8 9 10 11 12 Age 55 43# 25 29 40 30 37 7 10 60# 61 32 Sex F M F F F F M F M M F M Mutation status H67R ND H67R H67R H67R H67R H67R H67R H67R ND I553M I553M Immunodeficiency Infections URTI RTI URTI - URTI URTI URTI URTI - RTI RTI RTI Antibody deficiency Hypogammaglobulinemia, SAD ND Hypogammaglobulinemia, SAD - IgG subclass deficiency, SAD Hypogammaglobulinemia, SAD Hypogammaglobulinemia, SAD Hypogammaglobulinemia Hypogammaglobulinemia Hypogammaglobulinemia Hypogammaglobulinemia, SAD SAD Immunoglobulin replacement + - + - - + + - - - + - Immune dysregulation Febrile attacks - + + + - - + + - - - - Complex aphtae Mouth, genitalia ND Mouth, genitalia Mouth, genitalia - Mouth Esophagus Mouth, esophagus - - - - Arthritis Monoarthritis - Monoarthritis Monoarthritis - - - - - - Oligoarthritis - Gut disease Periodic abdominal pain, chronic idiopathic diarrhea ND Periodic abdominal pain, microscopic colitis Periodic abdominal pain - - - Periodic abdominal pain - ND Chronic idiopathic diarrhea Coeliac disease Other - Hyperinflammatory response and death after gallbladder surgery - Iritis, Hyperinflammatory response to tooth excision Kidney tumor - Rudimentary left kidney - - - Astma, hypothyreosis - URTI, upper respiratory tract infections; RTI, respiratory tract infections including recurrent pneumonia; SAD, Specific antibody deficiency; ND, No data; #Death age Figure 1. Family pedigrees. Figure 1. Family pedigrees. Disclosures Mustjoki: Sigrid Juselius Foundation: Research Funding; Signe and Ane Gyllenberg Foundation: Research Funding; the Finnish Cancer Societies: Research Funding; Novartis: Honoraria, Research Funding; Academy of Finland: Research Funding; Finnish Cancer Institute: Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Saarela:Roche: Honoraria.

With regard to their capacity for antibody induction, antigens can be classified as either T lymphocyte dependent (TD) or as T lymphocyte independent (TI).1 In the immune response to TD antigens, T lymphocyte help to B lymphocytes is essential for the regulation of B lymphocyte proliferation, production of immunoglobulins, immunoglobulin class switching, rescue of B lymphocytes from apoptotic death, germinal centre formation, and generation of B lymphocyte memory.2 In contrast to TD antigens, TI antigens induce antibody production without the help of T lymphocytes. TI antigens can be further divided into TI type 1 antigens (TI-1), which are polyclonal B lymphocyte activators (e.g. lipopolysaccharides), and TI type 2 (TI-2) antigens. TI-2 antigens are able to directly stimulate B lymphocytes. However, the antibody response to TI-2 antigens is somehow influenced by T lymphocytes.3 TI-2 antigens do not induce immunological memory and antibodies to TI-2 antigens in humans only develop after the age of 2 years.4,5 Generally, TI-2 antigens are antigens that consist of repetitive biochemical structures such as polymeric protein antigens, trinitrophenyl-ficoll (TNP-ficoll), and dinitrophenyl-ficoll (DNP-ficoll). A clinically important group among the TI-2 antigens are the bacterial capsular polysaccharides.6 Capsular polysaccharides of Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis are responsible for the bacterial virulence and antibodies to capsular polysaccharides provide protection against invasive infections with these bacteria.7 The delay in antibody formation to encapsulated bacteria renders infants and young children highly susceptible to infections with encapsulated bacteria, especially from the ages of 4 to 6 months on, when the placentally derived maternal IgG is metabolized.5 Therefore, children younger than 2 years of age are more at risk for invasive infections caused by encapsulated micro-organisms.8 Children with a persisting defect in the production of antibodies specific for pneumococcal capsular antigens after this age have the so-called ‘specific antibody deficiency with normal immunoglobulins’ (SADNI). They suffer from recurrent pneumococcal infections, although their immunoglobulin and immunoglobulin subclass levels and responses to protein antigens are normal.9–12 It is estimated that 5–10% of the children referred for evaluation of recurrent infections have SADNI and it is therefore highly important to understand the immunological background of the antibody formation against TI-2 antigens.13 In this review we will summarize the current understanding of how T lymphocytes modulate the antibody response against TI-2 antigens.

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)

To compare the efficacy of immunoglobulin replacement therapy given intravenously versus subcutaneously to prevent infections in patients with primary antibody deficiency syndromes, an international, multicenter, open label, crossover study was designed. Forty patients were randomized to receive either subcutaneous or intravenous immunoglobulin replacement therapy for 1 year. In the second year, patients were switched to the alternative treatment, enabling patients to act as their own controls. Equivalent doses were given by both routes. Ethical approval was obtained from the review boards of the hospitals in which the patients were seen and written consent obtained from each patient. Patients with a primary antibody deficiency syndrome, either common variable immunodeficiency or IgG subclass deficiency or specific antibody deficiency, who required immunoglobulin replacement therapy were included in the study. Patients were excluded if they had significant thrombocytopenia (defined as platelets less than 50 x 10(9)/liter), had high levels of anti-IgA antibodies (defined as greater than 1:8192), or had severe adverse reactions to a blood product within the last 2 years. The primary end point was the number of infections and their severity (moderate and major) during the two treatment periods. Secondary end points were adverse reactions, length of infections, days lost from school or work due to infections, and acceptability of treatment regimens to the patients. Based on the assumption that it was difficult to prove equivalence of therapies statistically in crossover studies, an arbitrary number of 40 patients was selected on the basis that this might be achievable in 2 years. There are no significant differences in efficacy or adverse reaction rates between immunoglobulin replacement therapy given subcutaneously or intravenously.

Cheng YK, Decker PA, O’Byrne MM, Weiler CR. Ann Allergy Asthma Immunol. 2006;97:306–311 PURPOSE OF THE STUDY. To study the clinical and laboratory characteristics of patients with specific polysaccharide antibody deficiency syndrome. STUDY POPULATION. This was a retrospective review of records obtained over 8 years of patients from the Mayo Clinic (Rochester, MN) who were found to have recurrent infection defined as ≥4 infections per year and an immunoglobulin G (IgG) level of >500 mg/mL. METHODS. Serious infections were defined as pneumococcal sepsis, meningitis, pneumonia, or deep-seated abscess. Specific polysaccharide antibody deficiency syndrome (SPADS) is empirically defined as RESULTS. Seventy-five patients met the inclusion criteria. The median age at presentation was 42 years (range: 0–76 years), and the median age at diagnosis was 48 years (range: 4–81 years). The median interval between onset of symptoms and diagnosis of SPADS was 4 years. Sixty-nine percent of the patients were female, and 83% were white. The most common documented infections (in order of occurrence) were sinus infection, pneumonia, bronchitis, and ear infections; only 7% of the patients had documented sepsis, meningitis, or deep-tissue abscesses. Eight percent had autoimmune disorder or rheumatic disease. Sixteen percent of the patients had 0 of 12 responses to Pneumovax; 72% had 1 to 6 of 12 responses; and 12% had 7 to 8 of 12 responses. Patients under 18 years of age tended to have less response. The median IgG2 level (150 mg/dL) for patients with 0 responses to Pneumovax tended to be lower compared with patients with >1 response (193 mg/dL; P = .06). When measured, the majority (31 of 35) of the patients had protective levels of antibody to tetanus and diphtheria (18 of 19). In vitro lymphocyte-stimulation test results were normal in the vast majority of patients when measured. Thirty patients were treated with a standard intravenous Ig (IVIg) therapy, 400 mg/kg per month for an undetermined time period. Patients with a higher number of infections (P = .003) and fewer responses to Pneumovax (P = .01) were more likely to receive IVIg. Of the patients receiving IVIg, the number of infections after treatment was significantly lower (median: 1 vs 8; P < .001). CONCLUSIONS. SPADS is a disorder of humoral immunity that is seen in patients with recurrent infections. Response to unconjugated pneumococcal vaccine is abnormal despite normal total IgG levels. Other immune abnormalities are not typically seen. Patients with more frequent infections have less responses to Pneumovax and may clinically respond to IVIg therapy. REVIEWER COMMENTS. This study was chosen for review because of the potential frequency of this problem in patients with recurrent infection. This descriptive, retrospective study had a very mixed population, and some of the patients included would not meet a rigorous definition of SPADS (some with autoimmune disease, poor response to protein antigens). The definition of an abnormal response to pneumococcal vaccination was not well established. The practice parameter for the diagnosis and management of primary immunodeficiency defines response to pneumococcal polysaccharide vaccine as postimmunization antibody concentration of >1.3 μg/mL or fourfold rise over baseline. Children younger than 2 years should not be given a diagnosis of SPADS, because they have a physiologic impairment of antibody production to unconjugated polysaccharide antigens. Prospective studies for a more specific definition and response to treatment are needed for patients with specific antibody deficiency and normal IgG levels.

The aim of this work was to define antibody levels against four neumococcal serotypes, before and after neumococcal vaccination in patients with respiratory infections. Fifty one patients were studied, 19 children from 1 to 5 years old; children from 6 to 18 years old and 22 adults from 27 to 65 years old. IgG anti-neumococcal, antibodies, against weeks after vaccination. There was a significant increase in antibody titers against all serotypes in subjects older 7 years. In children of less than 6 years, the response to serotype 14 was non significant. The intensity of response differed according to the studied serotype and the percentage of patients that responded to each serotype increased with age. Five patients older than 18 years were identified as non responders to all four serotypes. It is concluded that neumococcal vaccine increases anti-neumococcal antibodies in patients with recurrent infections and allows the identification of patients with specific antibody deficiency syndromes and normal total immunoglobulin levels.

Rationale To establish the antibody response rate in children with recurrent infections and fully immunized with the Pneumococcal 7-valent Conjugate vaccine. Methods We have analyzed 39 patients referred to our clinic with recurrent infections despite complete immunization with the Pneumococcal 7-valent Conjugate vaccine for age, according to ACIP guidelines. We assessed the patients by checking their immunization status and the antibody titers to all 7 Streptococcus pneumoniae serotypes included in the vaccine (4, 6B, 9V, 14, 18C, 19F, 23F) assessed by standardized ELISA. The patients were assembled into 3 groups, a non-immunized group with laboratory data prior to the vaccine, and an immunized group consisting of responders and non-responders according to their antibody titer (>1.3 or Results The mean age was 3.8 years for responders and 3.3 years for non-responders. There was no significant statistical difference between the groups regarding age, race and sex. Ten patients were identified who failed to respond to all 7 serotypes included in the Pneumococcal 7-valent Conjugate vaccine. There was no significant statistical difference between the non-immunized and the immunized non-responders to all 7 serotypes. Conclusions We have identified a special immunological phenotype of specific antibody deficiency (SAD) patients with normal total immunoglobulins and normal responses to protein antigens, but who failed to respond to conjugate pneumococcal polysaccharides.

Background Haemophilus influenzae type B (Hib) and Streptoccus pneumoniae are leading causes of LRTI in the severe asthma population. Patients attending our regional severe asthma service have functional antibody levels tested against these two bacteria. Those with weakened immune systems may go on to require immunoglobulin therapy. The prevalence and impact of specific antibody deficiency within the severe asthma population has yet to be established. Objective We sought to quantify the number of patients who are deficient in antibodies against Hib and S pneumoniae within the severe asthma population, both at initial assessment and after vaccination. Methods Data from our regional clinic stored on a National Severe Asthma database was supplemented with information from the UHSM clinical results database, which contains blood antibody levels against Hib and S pneumoniae and lung physiology. Deficiency in Hib was defined as antibody levels of S pneumoniae , 6 out of 12 strains tested measuring >0.35 μg/ml. Only patients assessed after January 2008 were included. The prevalence of radiological abnormality, Aspergillus sensitisation, blood and sputum eosinophil counts, and lung function between severe asthma patients with antibody deficiency, and those with normal antibody levels were then compared. Results Among the patients tested for immunity to S pneumoniae (n=94) and Hib (n=97), 33% and 51% respectively were found to be deficient at initial assessment. In patients with baseline immune deficiency, 70% of those that received the Pneumovax vaccine had persistently low antibody levels against S pneumoniae , (p=0.03), and 20% who received Menitorix remained deficient in Hib antibodies. The mean post bronchodilator FEV 1 for patients with normal S pneumoniae antibody levels was 82.4% predicted compared to 68.8% predicted in those who were deficient at initial assessment (p=0.018), and 65.3% predicted in patients with persistently low antibody levels even after vaccination (p=0.049). All other variables showed no difference between the groups. Conclusion This study demonstrates for the first time that antibody deficiency to S pneumoniae and Hib is common in patients with severe asthma, can persist despite vaccination in a significant proportion of individuals and is associated with worse lung function.

Wood P, Stanworth S, Burton J, et al. Clin Exp Immunol. 2007;149(3):410–423 PURPOSE OF THE STUDY. To create an evidence-based literature review of clinical diagnosis and management of primary antibody deficiency. METHODS. Computer literature searches were conducted for randomized clinical trials in medical literature databases including the US National Library of Medicine (Medline), the Excerpta Medica database (EMBASE), the Cochrane Library, the Database of Abstracts of Reviews of Effects (DARE) of the Centre for Reviews and Dissemination (University of York), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) up to June 2006. Reports were rated on the basis of relevance and quality or type of evidence. Disease entities included were X-linked agammaglobulinemia, common variable immunodeficiency, hyper–immunoglobulin M (IgM) syndromes, IgG subclass deficiency with and without IgA deficiency, and specific antibody deficiency. Reports that involved only a limited number of patients were not included. RESULTS. Individuals who present with recurrent respiratory infections of all types, especially with excessive frequency and severity, should be screened for antibody deficiency. In children, common associations included growth delay and failure to thrive, recurrent fevers without a source, and poor school attendance or performance. Chronic diarrhea was found in 40% to 60% of the patients at all ages. The median delay in diagnosis was 1 year but ranged to >10 years. Delayed diagnosis led to increased risk of bronchiectasis, pulmonary hypertension, and cor pulmonale. Randomized trials of the efficacy of γ-globulin replacement versus placebo do not currently exist. Many observational studies have confirmed the benefit of IgG therapy for reducing infectious morbidity. Higher IgG doses are associated with reduced incidence and severity of infections. CONCLUSIONS. Delayed diagnosis was common as a result of lack of recognition of presenting symptoms and signs. Delay was less frequent when patients were referred to specialists. Delayed diagnosis led to delayed therapy (IgG) and a higher rate of infections and morbidity. Several areas for additional research were identified, including studies of efficacy and dose of IgG and adjunct therapies (antibiotics), microbiologic study of pathogens, identification of prognostic markers, and effective monitoring of disease (eg, lung function, other organs, cancer). Collaboration and pooling of data among centers nationally and internationally would likely lead to better data. REVIEWER COMMENTS. This study again points out the human cost of delayed or undiagnosed immunodeficiency and the difficulties in accumulating high-quality data on therapy and outcomes. Several initiatives are taking shape in the United States and abroad to collaborate to answer many of the remaining questions pointed out in this study.

In recent years group B Streptococcus (GBS) has been recognized as a major perinatal pathogen. As with other encapsulated bacteria, protective immunity appears to correlate with serum antibody specific for the homologous capsular polysaccharide antigen of each serotype. Since susceptibility of the young infant to disseminated GBS infection relates to type-specific antibody deficiency in maternal serum, immunization of women with purified GBS type-specific polysaccharides has been proposed as a method for the prevention of infant disease through placental transport of protective antibodies. Candidate native polysaccharides from GBS have been purified, immunochemically and structurally characterized, and employed as immunogen in healthy adult volunteers. Native type Ia, II, and III polysaccharides have been shown to be nontoxic, safe, and immunogenic in approximately 65%, 95%, and 70%, respectively, of nonimmune adults. Antibody response to immunization approaches 100% in previously immune volunteers. Vaccine-induced type-specific antibodies to these candidate polysaccharide vaccines promote in vitro opsonophagocytosis, protect animals given a lethal challenge of homologous organisms, and are predominantly of the IgG isotype. Once similar results can be documented in women immunized during the last half of pregnancy, efficacy of these candidate GBS polysaccharide vaccines in the prevention of neonatal and young infant GBS disease should be evaluated.

The nature of the humoral immune defects in two unrelated patients with normal serum immunoglobulin and specific antibody deficiency was investigated. Five days after a booster immunization with soluble tetanus toxoid, peripheral blood lymphocyte B cells were assayed for the normal appearance of PWM and T-cell-independent antigen-specific IgG anti-tetanus lymphoblastoid B cells and suppressor T cells for these B cells. Patient 2 was totally unable to generate these B cells while patient 1 generated 10% of the normal tetanus specific B-cell activity. PBL samples were analyzed 21 days after immunization for PWM-dependent B-lymphocyte synthesis of total and anti-tetanus IgG and IgM and total and antigen-specific T-helper and -suppressor lymphocyte activity. Patient 1's B lymphocytes could generate normal amounts of both total and anti-tetanus IgG and IgM. However, his T lymphocytes completely suppressed IgG and anti-tetanus IgG production. Patient 2 also had excess radiation-sensitive T-suppressor cells for total and anti-tetanus IgG and IgM. However, this patient's B cells demonstrated an antigen-specific defect in culture in that they produced total IgG normally but were unable to produce specific anti-tetanus IgG. Thus, even with this small patient sample, the heterogeneity of immune defects established in other humoral deficiency diseases appears to exist in the syndrome of antibody deficiency with normal serum immunoglobulin.

Cartilage-hair hypoplasia (CHH) is a rare chondrodysplasia with short stature, hair hypoplasia, variable degree of immunodeficiency and increased risk of malignancy. The non-coding RNA gene RMRP is mutated in CHH. The gene has multiple functions, including cell cycle regualtion. Several aspects of CHH remain inadequately explored, including the pathogenesis, detailed characteristics of immunologic phenotype, correlations of clinical and laboratory features, as well as disease course and prognosis. To address these questions, we recruited and carefully examined a large cohort of Finnish children and adults with CHH. We performed detailed immunologic evaluation, explored the prevalence of bronchiectasis and compared the diagnostic performance of lung high-resolution computed tomography (HRCT) and magnetic resonance imaging (MRI). We also conducted a prospective 30-year follow-up study to identify factors associated with adverse outcomes. In addition, we investigated the role of telomere machinery in the pathogenesis of CHH by measuring relative telomere length (RTL). Study patients (n=56) demonstrated specific abnormalities in B and T cell compartments: 1) decreased thymic naive, naive CD4+ and CD8+ T cells; 2) increased activated CD4+, central memory CD4+ and effector memory CD8+ T cells; 3) normal regulatory T cells; 4) decreased naive, transitional and memory B cells; and 5) increased activated B cells. Specific antibody deficiency was demonstrated in the majority of patients immunized with unconjugated pneumococcal vaccine. No significant correlations were observed between clinical and laboratory features. Children with CHH demonstrated significantly shorter median RTL compared with healthy controls. HRCT showed bronchiectasis in 10/34 patients (29%), justifying lung evaluation also in those without apparent immunodeficiency. Lung MRI was comparable to HRCT in the assessment of bronchiectasis and could be implemented in the follow-up of lung changes. In the prospective study of 80 subjects with CHH, in a significant proportion of patients (17/79, 22%) clinical features of immunodeficiency progressed over time, including six cases of adult-onset immunodeficiency. Of the 15 subjects with non-skin malignancy, eight demonstrated no preceding symptoms of immunodeficiency. These findings call for careful follow-up and screening for cancer even in asymptomatic patients. Altogether 20/80 patients had died during the follow-up, and causes of death included pneumonia (n = 4), malignancy (n = 7) and pulmonary disease (n = 4). Increased mortality was associated with severe short stature at birth, Hirschsprung disease, pneumonia, autoimmunity and symptoms of combined immunodeficiency. In addition, warts in adulthood and actinic keratosis were associated with the development of skin cancer. The study findings should be considered when establishing management guidelines for patients with CHH. Rusto-hiushypoplasia (RHH) on harvinainen luustosairaus, jonka oireisiin kuuluvat kasvuhäiriön lisäksi hiusten hentous, elimistön puolustuskyvyn heikkous ja lisääntynyt syöpäriski. Huolimatta vuosien tutkimustyöstä, monet sairauden piirteet tunnetaan edelleen puutteellisesti. Sairauden solutason mekanismit, puolustuskyvyn yksityiskohtaiset ominaisuudet ja niiden yhteys oireisiin, sekä taudin kulku ja ennuste ovat edelleen osin tuntemattomia. Saadaksemme näistä seikoista lisätietoa, tutkimme suomalaisia RHH:aa sairastavia lapsia ja aikuisia. Teimme yksityiskohtaisen puolustuskyvyn arvioinnin, tutkimme kroonisten keuhkomuutosten esiintyvyyttä ja vertasimme eri kuvantamistutkimusten - keuhkojen tietokonetomografia (TT) ja magneettikuvaus (MK) – tarkkuutta keuhkomuutosten diagnostiikassa. Suoritimme myös 30-vuotisen seurantatutkimuksen ennusteeseen liittyvien tekijöiden tunnistamiseksi. Lisäksi tutkimme telomeerien piirteitä RHH:ssa mittaamalla suhteellisen telomeeripituuden. Immunologisiin tutkimuksiin osallistuneilla 56 potilailla löydettiin runsaasti muutoksia puolustussolujen kokonaismäärässä ja alaryhmissä sekä poikkeavat rokotevasteet. Oireiden ja laboratorioarvojen välillä ei havaittu merkittäviä yhteyksiä. Telomeerien pituus oli RHH:aa sairastavilla lapsilla huomattavasti lyhyempi kuin verrokeilla, viitaten RHH:n taustalla olevan geenivirheen vaikuttavan telomeerien ylläpitoon. Merkittävällä osalla potilaista löytyi keuhkoputkien laajenemia (bronkiektasioita) (10/34, 29%) TT-kuvauksella. Keuhkojen MK-tulokset olivat verrattavissa TT-tuloksiin keuhkoputkien arvioinnissa ja MK:ta voidaan siten käyttää keuhko-muutosten seurannassa. Keuhkojen tilanteen arviointi on aiheellista myös niillä RHH-potilailla, joilla ei ole merkkejä häiriintyneestä puolustuskyvystä. Laajassa 80 potilaan pitkäaikaisessa (keskimäärin 30 vuotta) seurantatutkimuksessa merkittävällä osalla potilaista (17/79, 22 %) puolustuskyvyn heikkous paheni iän myötä; kuudelle näistä potilaista kehittyi myöhäinen puolustuskyvyn heikkous aikuisiässä. Yli puolella syöpään (ihosyöpä pois lukien) sairastuneista potilaista (8/15, 53 %) ei ollut edeltäviä merkkejä häiriintyneestä puolustuskyvystä. Nämä löydökset ovat peruste potilaiden tarkkaan seurantaan ja syövän seulontaan myös oireettomilla potilailla. Seurannan aikana 80 potilaasta kuoli yhteensä 20, mm. keuhkokuumeeseen (4), syöpään (7) ja keuhkosairauksiin (4). Useat tekijät lisäsivät varhaisen kuoleman riskiä, mukaan lukien lyhyempi syntymäpituus, Hirschsprungin tauti, keuhkokuume, autoimmuunitaudit ja tietyt puolustuskyvyn poikkeavuudet. Lisäksi aikuisiän syylillä ja aurinkokeratoosilla oli yhteyttä ihosyövän kehittymiseen. Tutkimustuloksemme antavat arvokasta tietoa RHH:an piirteistä ja ennusteesta ja tuloksia voidaan hyödyntää potilaiden hoitosuositusten laadinnassa.

Primary immunodeficiency diseases (PIDs) are a genetically heterogeneous group disorders that affect distinct components of both humoral and cellular arms of the immune system (1,2). Overlapping signs and symptoms of these diseases is a challenge for diagnosis and treatment (3,4). Awareness of the symptoms and considering the possibility of PID in differential diagnosis help to rapid recognition and more appropriate treatment (2,5). Timely recognition and treatment reduced mortality and increased lifespan and quality of life of the patients (6). Memorization of all effective criteria to diagnosis is difficult, so developing a computerized program based on diagnosis criteria, improves significantly the quality of care (7,8).To develop the inference model to the diagnosis of PIDs, ontology has been used in this study. The study focused on eight common diseases of PIDs include Common Variable Immune Deficiency (CVID), X- Linked Agammaglobulinemia (Bruton’s) (XLA), Selective IgA Deficiency (SIgA), CD40L deficiency, UNG deficiency, Isolated immunoglobulin (Ig) G Subclass deficiency, Specific antibody deficiency (SAD) with normal Ig concentrations and normal numbers of B cells, Transient Hypogammaglobulinemia of infancy (THI) with normal numbers of B cells. Based on clinical guidelines and medical literature in PID (9), we designed a checklist to extract and classified most important signs and symptoms, family history, and laboratory data for eight main type of primary antibody deficiencies (PADs). To evaluate the quality of checklist, data for 100 cases in a different type of PADs were tested. Using frame-based ontology modeling to create the inference model and "Noy and McGuinness" method to develop the inference model. "Noy and McGuinness" method includes seven stages (10). Below we describe each stage of the method

Bronchiectasis is a chronic debilitating condition characterized by abnormal dilated thick-walled bronchi. To investigate humoral immune function in bronchiectatic patients, this study was performed. Forty patients with established diagnosis of bronchiectasis, who were referred from two tertiary care pulmonology centers in Tehran, were investigated in this study. Immunoglobulin isotypes concentrations and IgG-subclasses were measured by nephelometry and enzyme-linked immunosorbent assay (ELISA) methods, respectively. All patients received unconjugated pneumococcal vaccine, and blood samples were taken before and 21 days after vaccination. Specific antibodies against whole pneumococcal antigens were measured using the ELISA method. Fifteen (37.5%) out of 40 patients were diagnosed to have defects in antibody mediated immunity including 5 (12.5%) patients with immunoglobulin class deficiency (2 with common variable immunodeficiency and 3 with IgA deficiency), 3 (7.5%) with IgG subclass deficiency and 7 (17.5%) patients had Specific antibody deficiency (SAD) against polysaccharide antigen despite normal levels of serum immunoglobulins and IgG subclasses. Our study along with several other studies confirmed that all patients with bronchiectasis should undergo thorough immunological evaluation in order to identify the presence of the underlying immunologic defect. This evaluation should include serum immunoglobulins, IgG subclasses concentrations and also determination of serum antibodies against pneumococcal antigens. Early diagnosis and appropriate treatment will prevent the subsequent complications and improve quality of life of affected individuals.