Nima Pouladi

Clinical, Immunological and Molecular Characteristics of 37 Iranian Patients with X-Linked Agammaglobulinemia

Background: X-linked agammaglobulinemia (XLA) is a hereditary immunodeficiency characterized by an early onset of recurrent bacterial infections, a profound deficiency of all immunoglobulin isotypes and a markedly reduced number of peripheral B lymphocytes. Eighty-five percent of the patients with this phenotype have mutations in Bruton’s tyrosine kinase (BTK) gene. Methods: To provide an informative outlook of clinical and immunological manifestations of XLA in Iran, 37 Iranian male patients with an age range of 1–34 years, followed over a period of 25 years, were studied. Twenty-four of the 37 patients were screened for BTK gene mutation using PCR-SSCP followed by direct sequencing. BTK protein expression assay was done by flow cytometry in 9 families. Results: All patients first presented with infectious diseases, the most common of which were respiratory tract infections. Eighteen different mutations were identified, 13 of which were novel: IVS1+5G>C, 1896G>A, 349delA, 1618C>T, 1783T>C, 2084A>G, 1346delT, 1351delGAG, 587A>G, IVS14–1G>A, IVS3+2T>C, 1482G>A, 1975C>A. Conclusion: The fact that we found a great number of novel mutations in a relatively limited number of patients underlines the heterogeneity of BTK mutations in the Iranian population. The large number of new mutations indicates that extended studies in this region would be rewarding.

Immunologic evaluation of patients with recurrent ear, nose, and throat infections.

PURPOSE In this study, we aimed to study the frequency of possible underlying immunodeficiency responsible for susceptibility to ear, nose, and throat (ENT) infection. MATERIALS AND METHODS One hundred three (72 males and 31 females) consecutive children and adult patients with history of recurrent or chronic ENT infections, referred by otolaryngologists to the Department of Allergy and Clinical Immunology, Childrens Medical Center, Tehran University of Medical Sciences (Tehran, Iran), were enrolled to the study from March 2003 to March 2006. For each patient, demographic information and medical histories of any ENT infections were collected by reviewing the patients records. We measured immunoglobulin isotype concentrations and immunoglobulin (Ig) G subclasses by nephelometry and enzyme-linked immunosorbent assay methods, respectively. Of 103 patients, 75 received unconjugated pneumococcus polyvalent vaccine, and blood samples were taken before and 21 days after vaccination. Specific antibodies against whole pneumococcal antigens were measured using enzyme-linked immunosorbent assay method. Existence of bronchiectasis was confirmed in each patient using high resolution computed tomography scan. RESULTS Among 103 patients, 17 (16.5%) patients were diagnosed to have defects in antibody-mediated immunity including 6 patients with immunoglobulin class deficiency (2 common variable deficiency and 4 IgA deficiency), 3 with IgG subclass deficiency (2 IgG2 and 1 IgG3), and 8 with specific antibody deficiency against polysaccharide antigens. In our series, bronchiectasis was detected in 5 cases associated with primary immunodeficiency. CONCLUSIONS Long-standing history of ENT infections could be an alarm for ENT infections associated with primary antibody deficiency.

Genotype-phenotype correlation in Bruton's tyrosine kinase deficiency.

Brutons tyrosine kinase (Btk) belongs to the Tec family of nonreceptor protein tyrosine kinases. Mutations in the BTK gene cause X-linked agammaglobulinemia (XLA); a primary immunodeficiency disorder in human. No clear genotype-phenotype correlation has been established in XLA so far. To determine how differently mutations in BTK affect the severity of the disease and if BTK promoter polymorphic variant or intron 1 polymorphic variant in Tec, a cytoplasmic tyrosine kinase that might substitute for Btk, could contribute to the clinical phenotype, we analyzed the clinical and molecular findings in a cohort of XLA patients. Polymorphisms in BTK promoter and TEC intron 1 regions include substitutions of C>T (rs2071219) and T>C (rs2664019), respectively. Btk expression was evaluated by means of western immunoblotting and fluorescence-activated cell sorter analysis. Mutations were categorized as mild or severe and patients were evaluated for the clinical severity of disease. On the basis of the results, severe genotypes do not necessarily lead to severe phenotypes. More over, in a considerable number of patients with mild phenotype we showed a severe mutation with a tendency toward C substitution in the polymorphic site on TEC intron 1.

Progressive multifocal leukoencephalopathy in purine nucleoside phosphorylase deficiency.

Progressive multifocal leukoencephalopathy is a demyelinating disease caused by JC virus, an opportunistic infection of the central nervous system. Although the majority of cases are infected with the human immunodeficiency virus (HIV), other immunocompromised patients are also at risk. Purine nucleoside phosphorylase is an enzyme in the purine salvage pathway that reversibly converts inosine to hypoxanthine and guanosine to guanine. Purine nucleoside phosphorylase deficiency is a combined immunodeficiency with a profound cellular defect. Neurologic abnormalities are salient features of this syndrome. We describe for the first time a patient with this rare disorder presented with progressive multifocal leukoencephalopathy.

ENT manifestations in Iranian patients with primary antibody deficiencies

OBJECTIVE One hundred and nine patients with primary antibody deficiencies were selected in order to determine the frequency of ENT complications. METHOD Demographic information and ENT medical histories were collected for each patient. Duration of study for each patient was divided into two periods of before diagnosis and after diagnosis and the initiation of treatment. RESULTS Eighty-two of 109 patients (75.2 per cent) experienced ENT infections during the course of the disease (63: otitis media, 75: sinusitis and nine: mastoiditis). At the time of diagnosis, 52 (47.7 per cent) out of 109 patients presented with an ENT symptom. The frequencies of episodes were 27 for sinusitis and 25 for otitis media (one complicated with mastoiditis). After immunoglobulin replacement therapy the incidence of otitis media was reduced from 1.75 before treatment to 0.39 after treatment per patient per year (p = 0.008). The incidence of sinusitis also significantly decreased from 2.38 to 0.78 (p value = 0.011). CONCLUSION ENT infections are common medical problems in primary antibody deficiency patients. Persistent and recurrent ENT infections should be suspected as originating from a possible underlying immunodeficiency.