Hepatitis B virus (HBV) infection and its sequelae such as cirrhosis and hepatocellular carcinoma has remained a serious public health problem throughout the world. The WHO strategy for effective control of HBV infection and its complications is mass vaccination of neonates and children within the framework of Expanded Programme on Immunization (EPI). Vaccination with hepatitis B surface antigen (HBsAg) induces protective antibody response (anti-HBs ≥ 10 IU/L) in 90-99% of vaccinees.The lack of  response to  HBsAg has  been attributed  to a variety of  immunological mechanisms, including defect in antigen presentation, defect in HBsAg-specific T and/or B cell repertoires, T-cell suppression, increase in the regulatory T cell count, lack of necessary help of T-cells for production of anti-HBs by B cells, defect in Th1 and/or Th2 cytokine production  and  selective  killing  of  HBsAg-specific  B-cells  by  human  leukocyte  antigen (HLA)-restricted cytotoxic T lymphocytes. The HLA complex plays an important role in many of these immunological processes.A variety of HLA class I, II, and III alleles and antigens have been reported to beassociated with antibody response to HBsAg vaccination in different ethnic populations. Moreover, some HLA haplotypes were also associated with responsiveness to HBsAg.In this review the association of the HLA specificities with antibody response to hepatitis B (HB) vaccine is discussed.

Newly  identified  T  helper  cell  22  (Th22)  is  a  subset  of  CD4+T  cells  with  specific properties apart from other known CD4+ T cell subsets with distinguished gene expression and function. Th22 cells are characterized by production of a distinct profile of effector cytokines, including interleukin (IL)-22, IL-13, and tumor necrosis factor-α (TNF-α). The levels of Th22 and related cytokine IL-22 are increased in various autoimmune diseases and positively associated with some rheumatic diseases such as rheumatoid arthritis, systemic lupus erythematosus, behcet's disease, ankylosing spondylitis and psoriatic arthritis. In summary, IL-22 and Th22 cells play a significant and complicated role in inflammatory and autoimmune  rheumatic  diseases,  therefore,  targeting  IL-22  or  Th22  have  unique  and attractive advantages due to the fact that Th22 subset is recently identified and its associated research is extremely limited. This review discusses the role of Th22 and its cytokine IL-22 in the immunopathogenesis of rheumatic disease.

There are controversial reports regarding the role of peptidylarginine deiminase type 4 (PADI4) gene polymorphisms and risk of Rheumatoid arthritis (RA). The aim of the present study was to investigate the impact of PADI4 rs1748033 polymorphism and susceptibility to RA in a sample of the Iranian population.This case-control study was done on 150 patients with RA and 150 healthy subjects.PADI4 rs1748033 genotyping was done using amplification refractory mutation system- polymerase chain reaction (ARMS-PCR) assay.The  PADI4  rs1748033  variant  increased  the  risk  of  RA  in  codominant  (OR=1.67,95%CI=1.03-2.71, p=0.048, CT vs CC; OR=2.73, 95%CI=1.25-5.97, p=0.013, TT vs CC) and dominant (OR=1.84, 95%CI=1.15-2.92, p=0.014, CT+TT vs CC) tested inheritance models. In addition, the PADI4 rs1748033 T allele increased the risk of RA (OR=1.63,95%CI=1.16-2.29, p=0.006) in comparison with C allele.In conclusion, our finding indicated that PADI4 rs1748033 gene polymorphism increased the risk of RA in a sample of the Iranian population.

Activated macrophages have been classified into classical (M1) and alternative (M2) macrophages. We aimed to establish a method to yield enough number of macrophages to analyze their molecular, biological and immunological functions. We used drugs; adjuvant albumin from chicken egg whites—Imject Alum (OVA- Alum) and OVA Complete Freund Adjuvant (OVA-CFA), to induce macrophages to M2 and M1 respectively.We analyzed the phenotype of purified macrophages induced under these immune conditions, using flow cytometry (FACS) to detect cell-surface molecules and the enzyme-linked immunosorbent assay (ELISA) was used to detect cytokines. The cDNA microarray was employed to measure changes in expression level of cell surface protein between M1 and M2 macrophages.Phenotype   analysis   of   purified   macrophages,   induced   under   these   immune   conditions,   showed macrophages induced by OVA-Alum was almost M2 while the proportion of M1 macrophages induced by OVA-CFA was significantly higher. The results also showed higher expression level of macrophage galactose N- acetyl-galactosamine specific lectin-2 protein (MGL1/2-PE), a known M2 macrophage marker, on the surface of Alum-induced  macrophages.  On  the  basis  of  these  preliminary  data,  ELISA  results  revealed  that  after macrophage stimulation with lipopolysaccharides (LPS), the level of interleukin (IL)-10 produced by Alum- induced macrophages was higher than the level of IL-10 produced by CFA-induced macrophages. In contrast, the level of tumor necrosis factor-alpha (TNF-α) produced by CFA-induced macrophages was higher than Alum-induced macrophages.The cDNA microarray confirmed previous results and suggest immunoglobulin-like type 2 receptor alpha (Pilra) as a new marker for M1, macrophage galactose N-acetylgalactosamine-specific lectin 2 (Mgl2) as M2 macrophages marker.

The purpose of the present study is to investigate the prevalence of Th17 and regulatory T (Treg) cells in children with allergic rhinitis (AR) accompanying with bronchial asthma (BA).24 children with AR, 22 children with BA, 18 children with AR accompanying with BA,and 20 healthy controls were recruited. The prevalence of peripheral blood Th17 and Treg cells were determined by flow cytometry. mRNA expression of retinoid-acid receptor-related orphan  receptor  (ROR)-γt  and  forkhead  box  P3  (Foxp3) were  determined  by  realtime polymerase chain reaction. Cytokine expressions in plasma were determined by enzyme linked immunosorbent assay.The frequency of Th17 cells, ROR-γt mRNA expression, and the plasma levels of IL-17 were significantly higher, while Treg cells and Transforming growth factor (TGF)-β1 were significantly lower in children with AR accompanying with BA compared with those in children with AR or BA alone or control subjects. In children with allergic airway disease, total IgE levels were positively correlated to the frequency of Th17 cells (r=0.607, p<0.01), plasma IL-17 levels, and negatively correlated to the frequency of Treg cells (r=-0.429, p<0.01) and TGF-β1 levels (r=-0.224, p<0.01). While Forced expiratory volume in one second (FEV1) (% predicted) was negatively correlated to the frequency of Th17 cells (r=-0.602, p<0.01), plasma IL-17 levels (r=-0.577,  p<0.01), and positively correlated to  the frequency of Treg cells (r=0.504, p<0.01) and TGF-β1 levels (r=0.231, p<0.05).Our  results  demonstrate  that  the  imbalance  of  peripheral Th17/Treg  cells  plays  an important role in the pathogenesis of AR accompanying with BA.

Allergic rhinitis is a chronic respiratory disease. Sympathetic hypofunction is identified in all of the allergic rhinitis patients. Moreover, allergic rhinitis is associated with decreased peak nasal inspiratory flow (PNIF) and impaired lung functions. The aim of this study was to investigate effects of six-week of aquatic exercise on the autonomic nervous system function, PNIF and lung functions in allergic rhinitis patients.Twenty-six allergic rhinitis patients, 12 males and 14 females were recruited in this study. Subjects were diagnosed by a physician based on history, physical examination, and positive reaction to a skin prick test. Subjects were randomly assigned to two groups. The control allergic rhinitis group received education and maintained normal life. The aquatic group performed aquatic exercise for 30 minutes a day, three days a week for six weeks. Heart rate variability, PNIF and lung functions were measured at the beginning, after three weeks and six weeks.There were statistically significant increased low frequency normal units (LF n.u.), PNIF and showed decreased high frequency normal units (HF n.u.) at six weeks after aquatic exercise compared with the control group.Six weeks of aquatic exercise could increase sympathetic activity and PNIF in allergicrhinitis patients.

Asthma is a chronic inflammatory and remodeling disorder of the airways, in which many cells, cellular elements, and cytokines play important roles. The role of tumor necrosis factor- α (TNF-α) in asthma is unclear in Pakistani population. The aim of this study was to assess the relationship between TNF-α -308 polymorphism and asthma.Polymorphism of TNF-α (G-308-A locus; rs 1800629) in 329 asthmatic patients and 151 healthy  controls  was  evaluated.  DNA  was  prepared  from  blood  samples  of  cases  and controls. Samples were genotyped for TNF-α 308 G/A polymorphism.There was no significant difference in the frequency of GG (OR 1.049 with 95% CI 0.68-1.63) and GA (OR 0.987 with 95% CI 0.64-1.53) genotypes of TNF-α-308. The AA genotype was absent in cases and only one AA genotype was observed in the controls.The genetic polymorphism of TNF-α does not seem to be associated with asthma in Pakistani population.

The purpose of this study was to determine the clinical significance of changes in the plasma  adiponectin  concentration  in  patients  with  bronchial  asthma  and  to  test  the association between the single nucleotide polymorphisms (SNPs) rs2241766 and rs1501299 in the ADIPOQ gene and bronchial asthma in the Chinese Li population.We selected 120 cases and 120 controls, and plasma adiponectin, interleukin (IL)-6, and tumor  necrosis  factor-alpha  (TNF-α)  levels  were  measured  by  enzyme-linked immunosorbent assay (ELISA). In addition, we genotyped two tag single nucleotide polymorphisms (tSNPs) and evaluated their association with bronchial asthma using the χ2 test and genetic model analysis.Compared to controls, patients with acute exacerbation of bronchial asthma showedsignificantly lower adiponectin and significantly higher IL-6 and TNF-α levels (p<0.01). Apositive association was found between the rs1501299 SNP and acute exacerbation (OR =1.62; 95% CI= 1.08-2.43; p= 0.019).The inverse correlation between the plasma adiponectin concentration and asthma exacerbation indicates that adiponectin may play a protective role in the pathogenesis of asthma. Meanwhile, our findings suggest that ADIPOQ polymorphisms influence the risk of developing bronchial asthma in Chinese Li population.

Soluble forms of nonclassical human leukocyte antigen (HLA)-G have recently been suggested as immunomodulatory factors in multiple sclerosis (MS). HLA-G inhibits the effecter function of T cells and natural killer (NK) cells. Also regulatory T cells (Treg) are considered as pivotal players in MS pathogenesis. Thus, we aimed to evaluate the presence of HLA-G molecules and Treg cells in Relapsing-Remitting Multiple Sclerosis (RRMS) patients and compare it to healthy controls.Patients with RRMS (n=205, mean age=31.32±8.53) and healthy subjects (n=205, mean age=32.2±7.48) were studied. The patients subgrouped to untreated and treated with Interferon  beta.  Then  sHLA-G  levels  (sHLA-G1  and  sHLA-G5)  were measured  using ELISA method. Treg (CD4+CD25+  Foxp3+) cells in patients who had sHLA-G>10 U/ml were characterized by using flow cytometry.Our data showed that there was no significant differences between RRMS patients and healthy controls in  sHLA-G concentration (p>0.05). Treg cell frequencies were higher in the patients who had sHLA-G >10 U/ml compared to healthy subjects (p<0.05).Collectively, there was significant correlation between sHLA-G and frequency of Treg cells in treated RRMS patients and healthy individuals. It seems that high level sHLA-G has been  instrumental  in  raising  frequency  of  Treg  cells  in  treated  patients  and  could  be associated with remission of MS disease.

The association of HLA class II genes with ulcerative colitis (UC) as an autoimmune disease has been investigated for several years. However, factors responsible for genetic predisposition of this disease have so far not been clearly understood. In this study, for the first time, we aimed to investigate the association between HLA-DRB1 types and UC in the population of Kerman, a city southeast Iran. HLA typing was performed among 85 UC patients and 95 healthy controls using PCRamplification, employing sequence specific primers (PCR-SSP). The DRB1 frequencies were determined in the patients and controls. HLA-DRB1*04 was negatively associated with UC. Furthermore, HLA-DRB1*13 was significantly associated with severity of the disease (p=0.01) among UC patients. This is the novel result that describes an association of HLA-DRB1*13 with UC and also shows the protective role of HLA-DRB1*04 against the disease in people of Kerman.

The innate immune system utilizes pattern recognition receptors (PRRs) to recognize microbes. Pathogens contain various molecules with diverse effects on immune response. In this study, we evaluated the effect of DNA and protein components derived from two intracellular microorganisms including Listeria monocytogenes (L.monocytogenes) and Toxoplasma gondii (T. gondii) on dendritic cells (DCs) activation and ensuing adaptive immune responses.DNA and protein components of L. monocytogenes and T. gondii were prepared using relevant kits. DNA and protein components of these two pathogens were added to immature DCs (iDCs). Subsequently, co-stimulatory expression and cytokine production by DCs were measured. Finally, we evaluated the stimulatory capacity of mature DCs (mDCs) in DC-T cells co-culture.The results showed that protein matured-DCs produced higher level of IL (Interleukin)-12p70. There was also a significant increase in Interferon-Gamma (IFN-γ) production and proliferative capacity in T cells co- cultured with protein matured-DCs. On the other hand, DNA matured-DCs produced significantly higher amounts of Transforming growth factor-beta (TGF-β).Collectively, these results imply a regulatory nature for DNA and potent stimulatory character for protein components of these two intracellular microorganisms.

Our prior study found  that transforming growth factor  beta-induced (TGFBI) is  an important negative regulator in TLR-induced inflammation. However, whether TGFBI may affect inflammation during lipopolysaccharide (LPS)-induced endotoxin tolerance (ET) is still unclear.This study aimed to investigate whether TGFBI was involved in the mechanisms of ET in human through dampening nuclear factor-kappa B (NF-κB) mediated pathway. ET models of isolated healthy volunteers peripheral blood mononuclear cells (PBMCs) were established by pretreating with a low dose of LPS to observe the changes of TGFBI expression during ET induction, compared with ten healthy controls. Moreover, a vector-based short hairpin RNA expression system was used to specifically inhibit TGFBI expression to further explore its role in ET induction. The expression was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. The responses to LPS were determined by the activation of NF-κB, the production of tumor necrosis factor-α (TNF-α) and Nitric Oxide (NO), which were analysed by enzyme-linked immuno sorbent assay (ELISA).The results showed that TGFBI expression in the ET group obviously increased; ET also led to a hyporesponse of PBMCs to LPS with less activation of NF-κB, less production of TNF-α and NO, as well as more expression of TGFBI than those of non-ET group. Moreover, the inhibitory effect was partly refracted in plasmid TGFBI short hairpin RNA (pTGFBI-shRNA) transfected PBMCs. Meanwhile, the absence of TGFBI caused abnormal enhancement of inflammatory cytokine production and it was involved in ET induction through dampening NF-κB mediated pathway.Therefore, TGFBI may be a new target for the clinical treatment of inflammatory disorders.

Clericuzio-type poikiloderma with neutropenia (PN) is characterized by poikiloderma, non-cyclic  neutropenia,  recurrent  sinopulmonary  infections,  pachyonychia,  and  palmo- plantar hyperkeratosis. Mutations in the C16orf57 gene, which is located on chromosome 16q13, have been identified as the cause of PN. PN was first described by Clericuzio in Navajo Indians. Herein, we reported the clinical presentations and laboratory investigations of PN in three siblings from Turkey.The older siblings presented with typical cutaneous poikiloderma, plantar keratoderma, pachyonychia of toenails, and recurrent upper respiratory infections. As the most affected patient, in addition to classic manifestations, the youngest sibling had recurrent pneumonia, hepatosplenomegaly, dental caries, failure to thrive, and hand malformation.Genetic study revealed a homozygous mutation (c.531delA) in the C16orf57 gene in siblings.With the presented study, we aimed to draw attention to PN which can be a predisposing factor to malignancies.

Churg-Strauss syndrome (CSS) is a granulomatous small vessel vasculitis . It is characterized by asthma, allergic granulomatosis and vasculitis . This syndrome is rare in children. A 5 years old boy was admitted with cough, fever and dyspnea for 2 weeks. On the basis of  laboratory data (peripheral eosinophilia), associated with skin biopsy, and history of CSS in his sister, this disease was eventually diagnosed. The patient had good response to corticosteroid.In  every  asthmatic  patient  with  prolonged  fever, eosinophilia  and  multisystemic involvment, CSS should be considered.

LETTER TO THE EDITOR