B cells and T cells abnormalities in patients with selective IgA deficiency.

BACKGROUND: Selective IgA deficiency (SIgAD) is the most prevalent inborn errors of immunity with almost unknown etiology. This study aimed to investigate the clinical diagnostic and prognostic values of lymphocyte subsets and function in symptomatic SIgAD patients. METHODS: A total of 30 available SIgAD patients from the Iranian registry and 30 age-sex-matched healthy controls were included in the present study. We analyzed B and T cell peripheral subsets and T cell proliferation assay by flow cytometry in SIgAD patients with mild and severe clinical phenotypes. RESULTS: Our results indicated a significant increase in naïve and transitional B cells and a strong decrease in marginal zone-like and switched memory B-cells in SIgAD patients. We found that naïve and central memory CD4+ T cell subsets, as well as Th1, Th2 and regulatory T cells, have significantly decreased. On the other hand, there was a significant reduction in central and effector memory CD8+ T cell subsets, whereas proportions of both (CD4+ and CD8+) terminally differentiated effector memory T cells (TEMRA) were significantly elevated in our patients. Although some T cell subsets in severe SIgAD were similar, a decrease in marginal-zone and switched memory B cells and an increase in CD21low B cell of severe SIgAD patients were slightly prominent. Moreover, the proliferation activity of CD4+ T cells was strongly impaired in SIgAD patients with a severe phenotype. CONCLUSION: SIgAD patients have varied cellular and humoral deficiencies. Therefore, T cell and B cell assessment might help in better understanding the heterogeneous pathogenesis and prognosis estimation of the disease.

Potential therapeutic applications of extracellular vesicles in the immunopathogenesis of COVID-19.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19) which has emerged as a global health crisis. Recently, more than 50 different types of potential COVID-19 vaccines have been developed to elicit a strong immune response against SARS-CoV-2. However, genetic mutations give rise to the new variants of SARS-CoV-2 which is highly associated with the reduced effectiveness of COVID-19 vaccines. There is still no efficient antiviral agent to specifically target the SARS-CoV-2 infection and treatment of COVID-19. Therefore, understanding the molecular mechanisms underlying the pathogenesis of SARS-CoV-2 may contribute to discovering a novel potential therapeutic approach to the management of COVID-19. Recently, extracellular vesicle (EV)-based therapeutic strategies have received great attention on account of their potential benefits in the administration of viral diseases. EVs are extracellular vesicles containing specific biomolecules which play an important role in cell-to-cell communications. It has been revealed that EVs are involved in the pathogenesis of different inflammatory diseases such as cancer and viral infections. EVs are released from virus-infected cells which could mediate the interaction of infected and uninfected host cells. Hence, these extracellular nanoparticles have been considered a novel approach for drug delivery to mediate the treatment of a wide range of diseases including, COVID-19. EVs are considered a cell-free therapeutic strategy that could ameliorate the cytokine storm and its complications in COVID-19 patients. Furthermore, EV-based cargo delivery such as immunomodulatory agents in combination with antiviral drugs may have therapeutic benefits in patients with SARS-CoV-2 infection. In this review, we will highlight the potential of EVs as a therapeutic candidate in the diagnosis and treatment of COVID-19. Also, we will discuss the future perspectives regarding the beneficial effects of Evs in the development of COVID-19 vaccines.

Circulating miR-21 Overexpression Correlates with PDCD4 and IL-10 in Systemic Lupus Erythematosus (SLE): A Promising Diagnostic and Prognostic Biomarker.

Background: Systemic Lupus Erythematosus (SLE) is a chronic autoimmune condition that affects multiple organs significantly impacts morbidity and mortality. The development of SLE is influenced by genetic predisposition and dysregulated immune response. Our objective was to investigate miR-21, IL-10, and PDCD4 expression in SLE patient plasma and analyze their correlations and potential diagnostic and prognostic values. Methods: The study included 100 healthy subjects, 50 newly diagnosed (ND), and 50 under-treatment (UT) SLE patients. The patients were observed for 24 weeks to track relapses. miR-21 and PDCD4 gene expression levels were measured using real-time RT-PCR, and IL-10 production was measured using ELISA. Results: miR-21 and IL-10 expression levels were significantly greater in SLE patients than in healthy subjects, with the highest levels observed in ND patients. PDCD4 expression was also significantly greater in SLE patients than in subjects, with the highest levels observed in UT patients. ROC curve analyses and Cox-Mantel Log-rank tests indicated miR-21, PDCD4, and IL-10 as proper diagnostic and prognostic biomarkers for SLE. The study also revealed a significant positive correlation between miR-21 and PDCD4 and IL-10 levels in SLE patients. Conclusions: The studies suggest that dysregulation of miR-21, PDCD4, and IL-10 in patients with SLE may contribute to disease development and provides new diagnostic and prognostic markers. Additionally, the observed correlation between miR-21, PDCD4, and IL-10 levels in SLE patients signifies a potential interplay between these molecules.

Evaluation of effective factors on IL-10 signaling in B cells in patients with selective IgA deficiency

Background: Selective IgA deficiency is the most prevalent form of primary immunodeficiencies. The pathogenesis of the disease is still unknown. Several studies have suggested a defect in B cell responses to IL-10; however, the main reason for this defect has not been reported. Elucidating IL-10 signaling defects and their correlation with clinical manifestations could be helpful for better understanding and treatment of the disease. Methods: In this study, 15 SIgAD patients and 15 age- and sex-matched healthy controls were included. Surface expression of transforming growth factor ß receptor II (TGF-ß RII), IL-10R and IgA was assessed by flow cytometry in human purified B cells before and after stimulation by IL-10. Protein expression of STAT3, p-STAT3 and SOCS3 was measured by Western blotting analysis. TGF-ß and IgA secretion was evaluated by ELISA. Finally, the measurement of B cell apoptosis was performed by flow cytometry. Results: The TGF-ßRII expression level was decreased after stimulation with IL-10 in patients compared with controls. Notably, the TGF-ß level were higher after stimulation with mCD40L and IL-10 in the control group as compared to stimulation with mCD40L alone. The IgA+ B cell percentage and IgA secretion levels were significantly increased in controls as compared with SIgAD patients. The relative concentration of the total STAT3 was decreased as compared with controls. Conclusion: The defect in IgA production in SIgAD patients could be due to inadequate B cell responses to IL-10 stimulation that probably originate from defective regulation of IL-10-mediated TGF-b 'symbol' production TGF-ß response by IL-10. Furthermore, it is suggested that the absence of STAT3 protein baseline expression could impair cytokine-mediated signaling such as thatinduced by IL-!0 and IL-21.

Evaluation of Specific Antibody Responses in Patients with Selective IgA Deficiency and Ataxia Telangiectasia.

BACKGROUND: Specific Antibody Deficiency (SAD) is a primary immunodeficiency disease (PID) characterized by the occurrence of recurrent infections and inadequate antibody response to polysaccharide new antigens. OBJECTIVE: This study aims to determine the titer of specific antibodies against unconjugated 23-valent pneumococcal polysaccharide vaccine (PPSV-23), the presence of SAD, and its association with clinical and laboratory findings in Ataxia-telangiectasia (A-T) and selective immunoglobulin A deficiency (SIgAD) patients. METHODS: 32 A-T patients and 43 SIgAD patients were included in this cross-sectional study. Samples of the patients were obtained before and three weeks after vaccination with PPSV-23. Specific immunoglobulin G (IgG) directed towards pneumococcal capsular antigen and specific antibodies against whole pneumococcal antigens was measured. RESULTS: Comparison of the response to vaccination revealed that 81.3% of A-T patients and 18.6% of the SIgAD patients had an inadequate response to PPSV-23 (p<0.001). The prevalence of recurrent infection (p=0.034) and pneumonia (p=0.003) in SIgAD patients was significantly higher in non-responders than responders. Likewise, the number of marginal zone B cells (p=0.037), transitional B cells (p=0.019), plasmablasts (p=0.019), CD8+ naïve T cells (p=0.036), and percentage of CD8+ T cells (p=0.047), switched memory B cells (SMB) (p=0.026) and immunoglobulin M (IgM) memory B cells (p=0.022) in SIgAD patients were significantly lower in non-responder group than responder group. In contrast, the percentage of CD4 T+ cells in A-T patients was lower in the non-responder group than responders (p=0.035). CONCLUSION: SAD is more frequent in A-T patients than SIgAD patients. The role of SMB and T cells should not be underestimated in SAD.

Evaluation of Expression of LRBA and CTLA-4 Proteins in Common Variable Immunodeficiency Patients.

Common variable immunodeficiency (CVID) is a primary immunodeficiency disease with a heterogeneous genetic background. Lipopolysaccharide-responsive beige-like anchor (LRBA), as well as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have important regulatory roles in the immune responses. Here, we have investigated the expression of LRBA and CTLA-4 proteins in CVID patients with at least one presentation of early-onset occurrence, autoimmunity, or enteropathy. In this study, 20 newly diagnosed CVID patients without infection only phenotype, and ten healthy individuals were enrolled. The expressions of LRBA and CTLA-4 proteins were assessed by western blotting and flow cytometry, respectively. The patients were divided into two groups of autoimmunity-positive (11 cases) and autoimmunity-negative (9 patients). LRBA and CTLA-4 expressions were significantly lower in autoimmune-positive patients than in healthy individuals (P = .03 and P = .03, respectively). Autoimmune-negative patients had lower expression of LRBA and CTLA-4 than the control group, although it was not significant. There was a positive correlation between the expressions of LRBA and CTLA-4 in both groups of patients (P < .05). Furthermore, the highest frequency of LRBA (85.7%) and CTLA-4 (71.4%) defects was detected in those with concomitant presence of autoimmunity, enteropathy, and early-onset occurrence. Concurrent presence of autoimmunity, enteropathy, and early-onset occurrence in CVID patients could be indicative of a lack of expression in LRBA and CTLA-4 proteins. This could be helpful in early diagnosis and initiation of appropriate treatment in these patients prior to genetic confirmation.

Lymphocytes subsets in correlation with clinical profile in CVID patients without monogenic defects.

Objectives: Common variable immunodeficiency (CVID) patients experience clinical manifestations rather than recurrent respiratory infections including autoimmunity, enteropathy, and lymphoproliferation. We evaluated the correlation of lymphocyte subpopulations with such manifestations.Methods: Twenty-six genetically unsolved CVID patients were subdivided into four phenotypes: infection only (IO), autoimmunity (AI), chronic enteropathy (CE), and lymphoproliferative disorders (LP) and examined for lymphocyte subsets by flow cytometry and TCD4+ proliferation by Carboxyfluorescein succinimidyl ester (CFSE) test.Results: We detected reduced memory B and increased total, effector memory (EM), cytotoxic, and activated TCD8+ in IO, AI and CE, decreased plasmablasts, total and naive TCD4+, Regulatory TCD4+ (Treg) and naive TCD8+ in IO and CE, elevated CD21low B and terminally differentiated effector memory (TEMRA) TCD8+ in IO and AI, increased helper T (Th2) and Th17 in IO, decreased Th1 in AI and defective total and naive B and central memory (CM) TCD4+ in CE. IO showed reduced TCD4+ proliferation response.Conclusions: In genetically unsolved CVID patients, increased Th2 and Th17 and reduced Treg is associated with IO, increased CD21low B and TEMRA TCD8+ and reduced Th1 is contributed to AI and reduced total and naive B, CM TCD4+ and naive TCD8+ and expanded total TCD8+ is correlated with CE.

The fatty acid-binding protein (FABP) decreases the clinical signs and modulates immune responses in a mouse model of experimental autoimmune encephalomyelitis (EAE).

BACKGROUND: An increasing body of studies has shown that Fasciola hepatica can affect immune responses. This study explored whether the fatty acid-binding protein (FABP) of F. hepatica can modulate the immune system in a mouse model of experimental autoimmune encephalomyelitis (EAE). METHODS: EAE-induced C57BL/6 mice were treated with vehicle, F. hepatica total extract (TE) or FABP. The clinical signs, body weights, and the expression of IFN-γ, T-bet, IL-4, GATA3, IL-17, RORγ, TGF-ß, FOXP3, IL-10, TNF-α genes and proteins were determined in the isolated CD4+ splenocytes. Besides, the percentage of Treg cells and degree of demyelination were evaluated. RESULTS: We found that TE and FABP treatments decreased the clinical scores, lymphocyte infiltration rate, and demyelinated plaques in EAE mice. The expressions of IL-4 and GATA3 were increased, whereas IL-17 and TNF-α were down-regulated. FABP did not affect the expression of IFN-γ, RORγ, IL-10, and TGF-ß genes or proteins but reduced the expression of T-bet. TE administration did not affect the expression of IL-10 and the Tbet genes, and increased the expression levels of IFN-γ and FOXP3 in CD4+ lymphocytes. Both FABP and TE treatment did not affect the Treg cell percentage. CONCLUSION: This study indicates that F. hepatica FABP and TE can suppress the inflammatory responses in EAE-induced mice and shift the immune system toward Th2 responses. However, FABP exerts stronger anti-inflammatory effects and seems to be more effective than TE for EAE treatment.

Anti-Inflammatory Effect of KW-2449 on Autoimmune Encephalomyelitis: An Experimental Study on Mice.

BACKGROUND: The KW-2449 is a novel multikinase inhibitor that inhibits FLT3, ABL, ABL-T315I, and Aurora A. FLT3 and Aurora A kinases play an important role in the pathogenesis of multiple sclerosis (MS). KW-2449 could modulate immune cells, but the immunomodulatory effects of KW-2449 on experimental autoimmune encephalomyelitis (EAE) have not been investigated yet. The aim of the present study is to investigate the effects of KW-2449 on EAE mouse model. METHODS: In this study, C57BL/6 EAE mice were orally treated with (10 mg/kg/day) KW-2449 solution and compared with EAE and control mice. Following the treatment, histological analyses were performed on the brain and cerebellum to evaluate the pathological score. The gene expression levels of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and chemokine (C-C motif) ligand 2 (CCL2) were measured using qRT-PCR. The serum levels of TNF-α, IL-6, CCL-2 and MMP-2 were determined by using quantitative enzyme-linked immunosorbent assay (ELISA). RESULTS: The results indicated that the clinical score, the infiltration of inflammatory cells and the demyelination in EAE mice treated with KW-2449 decreased significantly compared to control groups. KW-2449 also decreased TNF-α, IL-6, CCL-2 inflammatory cytokines, and MMP-2 in both brain mRNA expressions and serum levels of EAE mice. CONCLUSION: The KW-2449, aging as a multi-kinase inhibitor, modulates the inflammatory responses of cytokine cascades either in the brain or in plasma and reduces EAE pathogenesis manifestation.

Evaluation of Radiation Sensitivity in Patients with Hyper IgM Syndrome.

BACKGROUND: HIGM syndrome is a rare form of primary immunodeficiencies characterized by normal/increased amounts of serum IgM and decreased serum levels of other switched immunoglobulin classes. Since the affected patients are continuously infected with various types of pathogens and are susceptible for cancers, diagnostic and therapeutic tests including imaging techniques are recommended for the diagnosis and treatment of these patients, which predispose them to higher accumulated doses of radiation. Given the evidence of class switching recombination machinery defect and its association with an increased rate of DNA repair, we aimed to evaluate radiation sensitivity among a group of patients diagnosed with HIGM syndrome. METHODS: 19 HIGM patients (14 CD40 L and 3 AID deficiencies and 2 unsolved cases without known genetic defects) and 17 control subjects (10 healthy subjects as negative control group, 7 ataxia-telangiectasia patients as positive control group) were enrolled. G2 assay was carried out for the determination of radiosensitivity. RESULTS: Based on radiation-induced chromosomal changes among the studied HIGM patients and their comparison with the controls, almost all (95%) the patients had degrees of radiosensitivity: 6 patients with low to moderate, 1 patient with moderate, 11 patients with severe and 1 patient without radiation sensitivity. CONCLUSION: Today, X-ray radiation plays a very important role in diagnostic and therapeutic procedures; while increased exposure has devastating effects especially in radiosensitive patients. Considering higher sensitivity in HIGM patients, utilizing radiation-free techniques could partly avoid unnecessary and high-level exposure to radiation, thus preventing or reducing its harmful effects on the affected patients.

Prevalence and antibiotic resistance of Acinetobacter baumannii among patients in postcardiac surgery intensive care units of Rajaei Hospital, Tehran.

Background: Acinetobacter baumannii is an opportunistic, aerobic, nonfermentative, Gram-negative bacterium that can cause major nosocomial infections, especially in patients hospitalized in intensive care units (ICU). Recently, A. baumannii strains have been resistant to a variety of antibiotics. Thus, it was aimed to evaluate the prevalence of A. baumannii and their resistance to the antibiotics in the patients hospitalized in postcardiac surgery ICU. Methods: This retrospective cross sectional study was performed in Rajaei hospital between March 2014 and February 2016. A. baumannii strains were isolated from blood cultures, catheter cultures, sputum cultures, and wound smear cultures. Then, isolates were characterized using standard morphological, cultural, and biochemical properties according to CLSI 2016. The frequency of A. baumannii species were reported as percent. Results: Among 27 167 patients were admitted to the ICU, 113 individuals, including 55 males and 58 females, were identified as A. baumannii-infected and the prevalence rate was 0.42%. The highest rates of antibiotic sensitivity were related to Meropenem 20 (17.7%) and Colistin 16 (14.1%). The shortest length of stay (LOS) for patients with A. baumanniiin the ICU was 3 days, while the longest LOS was 98 days. Conclusion: The findings indicated that A. baumannii strains isolated from postcardiac surgery ICUs had a high prevalence and were sensitive to Meropenem and Colistin. However, new molecular-based techniques are needed to monitor nosocomial infections. Therefore, the treatment of the patients may be feasible by appropriate antibiotic therapy, and infection control policies will be improved by adopting precise disinfection strategies.

Diagnostic Approach to the Patients with Suspected Primary Immunodeficiency.

BACKGROUND AND OBJECTIVE: Primary immunodeficiency diseases (PIDs) are a group of more than 350 disorders affecting distinct components of the innate and adaptive immune systems. In this review, the classic and advanced stepwise approach towards the diagnosis of PIDs are simplified and explained in detail. RESULTS: Susceptibility to recurrent infections is the main hallmark of almost all PIDs. However, noninfectious complications attributable to immune dysregulation presenting with lymphoproliferative and/or autoimmune disorders are not uncommon. Moreover, PIDs could be associated with misleading presentations including allergic manifestations, enteropathies, and malignancies. CONCLUSION: Timely diagnosis is the most essential element in improving outcome and reducing the morbidity and mortality in PIDs. This wouldn't be possible unless the physicians keep the diagnosis of PID in mind and be sufficiently aware of the approach to these patients.

The Heterogeneous Pathogenesis of Selective Immunoglobulin A Deficiency.

Selective immunoglobulin A deficiency (SIgAD) is the most prevalent type of primary immunodeficiency disorder. The phenotypic feature of SIgAD is related to a defect in B lymphocyte differentiation into plasma cell-producing immunoglobulin A (IgA). In this review, we summarize the recent advances in this regard. Genetic (including major histocompatibility complex [MHC] and non-MHC genes), immunologic (including B and T lymphocyte subsets abnormality), cytokines/chemokines and their related receptors, apoptosis and microbiota defects are reviewed. The mechanisms leading to SIgAD are most likely multifactorial and it can be speculated that several pathways controlling B cells functions or regulating epigenetic of the IGHA gene encoding constant region of IgA heavy chain and long-term survival of IgA switched memory B cells and plasma cells may be defective in different SIgAD patients.

Comparison of clinical and immunological features and mortality in common variable immunodeficiency and agammaglobulinemia patients.

Common Variable Immunodeficiency (CVID) and agammaglobulinemia are two of the main types of symptomatic primary antibody deficiencies. The pathogenic origins of these two diseases are different; agammaglobulinemia is a group of inherited disorders that usually are caused by mutations in the gene encoding Bruton Tyrosine Kinase (BTK) protein while CVID is a heterogeneous disorder mainly without monogenic cause. However, both diseases share a characteristic of frequent bacterial infections, a decline in serum immunoglobulin levels, and abnormality in antibody responses. The demographics and immunologic parameters, clinical manifestation, and mortality statistics from 297 patients with CVID and agammaglobulinemia followed up over 2 decades in the Children's Medical Center of Iran. Age at onset of symptom in agammaglobulinemia was earlier than CVID but the course of disease in CVID patients was longer than agammaglobulinemia patients. Pulmonary infections were the most prevalent clinical manifestations in both groups of patients. Lymphadenopathy, hepatomegaly, and splenomegaly were significantly higher in CVID patients than agammaglobulinemia patients and there was a significant association between these complications and mortality in CVID patients. Among 297 patients, 128 patients (88 CVID and 40 agammaglobulinemia) deceased. The predominant causes of death in CVID patients were infections, chronic lung disease, and malignancy while in agammaglobulinemia patients were infections and respiratory failure. Infections, especially respiratory infections were the most common complication and cause of death in both CVID and agammaglobulinemia groups and recent treatment advances even Immunoglobulin replacement cannot completely control these complications. Thus prompt recognition and specific management of these complications are worthwhile.

IL-10 induces TGF-ß secretion, TGF-ß receptor II upregulation, and IgA secretion in B cells.

Interleukin-10 (IL-10) is a pleiotropic cytokine, which has both regulatory and stimulatory effects on different immune cell types. Different studies have reported the importance of IL-10 and Transforming growth factor-beta (TGF-ß) in the regulation of B cell class switching the production of immunoglobulin A (IgA); however, the underlying mechanisms remain to be fully elucidated. The objective of this study was to investigate the TGF-ß response during B stimulation of human B cells by IL-10. Pan B cells of healthy donors were negatively purified by a magnetic cell separation technique. B cells were cultured with multimeric CD40 ligand (mCD40L) and IL-10 for two and seven days. After harvesting in specific days, TGF-ß receptor II and surface IgA expression was determined by flow cytometry, while IgA and TGF-ß secretion was assessed by enzyme-linked immunosorbent assay. B cells endogenously expressed TGF-ß receptor II and after 48 hours cultivation with mCD40L or mCD40L plus IL-10, both the expression of this receptor and the production of TGF-ß were significantly increased. Notably, TGF-ß levels following stimulation with mCD40L and IL-10 were higher than those produced by B cells stimulated with mCD40L alone. Furthermore, at day 7 and following IL-10 stimulation, there was a significant rise in the amount of IgA secretion by class-switched plasma cells, which was higher than stimulation with mCD40L alone. Our findings suggest that IL-10 can modulate TGF-ß production and TGF-ß receptor expression in mCD40-activated human B lymphocytes.

The Clinical and Immunological Features of Patients with Primary Antibody Deficiencies.

BACKGROUND: Primary antibody deficiency (PAD) comprises a range of diseases from early to late terminal B cells defects and is associated with the various clinical complications. METHODS: A total of 461 patients (311 males and 150 females) with PADs enrolled in the retrospective cohort study and for all patients' demographic information, clinical records and laboratory data were collected to investigate clinical complications. RESULTS: The most prevalent first presentations of immunodeficiency were respiratory tract infections in 63.5% and chronic diarrhea in 17.2%. Common variable immune deficiency (CVID) patients had a higher diagnostic delay than class switching defect (CSD), and agammaglobulinemia. Among the noninfectious complications, autoimmunity (26.2%), and splenomegaly (23.4%) were the most common. Lymphadenopathy was higher in CSD patients than other PADs, while splenomegaly, hepatomegaly, autoimmunity and bronchiectasis were more common in CVID patients than others. Atopic manifestations were mostly recorded in patients with selective IgA deficiency. Malignancy was only reported in 5.8% of patients with CVID. There was a higher prevalence of autoimmune manifestations in CVID comparing to other PADs. CONCLUSION: PADs are relatively rare diseases and these patients have a variety of first clinical manifestations, such as diverse infections, autoimmunity, lymphoproliferation, allergy, enteropathy and malignancy. Practitioner's awareness about the heterogeneous presentations of PAD disorders is poor, therefore patients often are lately diagnosed, and they are complicated with several clinical complications before the certain diagnosis.

Autoimmunity in a cohort of 471 patients with primary antibody deficiencies.

OBJECTIVES: The aim of this study was to evaluate the frequency of autoimmunity in primary antibody deficiency (PAD). METHODS: A total of 471 patients with PADs enrolled in this retrospective cohort study. For all patients' demographic information, clinical records and laboratory data were collected to investigate autoimmune complications. RESULTS: Autoimmune disorders as the first presentation of immunodeficiency were recorded in 11 patients (2.5%). History of autoimmunity was recorded in 125 patients during the course of the disease (26.5%). The frequency of autoimmunity in common variable immune deficiency (32.0%) was higher than other forms of PADs. The most common autoimmune manifestations were reported to be autoimmune gastrointestinal disease and autoimmune cytopenias. Among patients with autoimmunity, 87 patients (69.6%) had a history of one autoimmune disorder, while 38 patients (30.4%) had a history of multiple autoimmunities. The immune thrombocytopenic purpura and autoimmune hemolytic anemia were the most two concomitant autoimmune disorders in 16 (42.1%) of 38 patients with multiple autoimmunities. Comparing the frequency of Tregs in PAD patients with autoimmunity showed that, patients with multiple autoimmunities had lower Tregs than those with single autoimmunity (p = 0.017). CONCLUSION: It is important that non-immunologist physicians be alert of the associated autoimmunity with PADs in order to reduce the diagnostic delay and establish timely immunoglobulin replacement therapy in these patients.