Iranian journal of immunology
Volume:18 Issue: 3, Summer 2021

Neuro-Behcet's disease (NBD) is a rare but potentially fatal manifestation of Behcet's disease. Common presentations of neuro-Behcet's disease are parenchymal (brainstem manifestations, hemispheric manifestations, meningoencephalitis, spinal cord lesions) and non-parenchymal (arterial occlusions, aneurysms, Dural sinus thrombosis). Cerebrospinal fluid (CSF) findings in parenchymal NBD usually show an inflammatory pattern with elevated cell count (usually high levels of polymorphonuclear leukocytes), high protein, and normal glucose levels, whereas the CSF findings in non-parenchymal NBD could be normal except for high opening pressure. Further investigation of CSF in parenchymal NBD has demonstrated elevated Natural killer T cells, high inflammatory chemokines, and cytokines such as Tumor Necrosis Factor-alpha (TNF- α), Interferon-gamma (IFN-γ), Interleukin (IL)12, IL-6, IL-17, IL-26, IL-15, Vascular endothelial growth factor (VEGF), Matrix metallopeptidase 9 (MMP-9), chemokine [C-X-C motif] ligand 8 (CXC-8) which indicate the role of both innate and adaptive immunity in this disease. Particularly, T helper type 1 (TH-1) and TH-17pathways are implicated in the pathogenesis of this condition. Successful use of certain biologic agents such as the TNF inhibitors and IL-6 inhibitors in NBD further emphasizes the role of inflammatory cytokines in the immunopathogenesis of the disease. Drugs blocking the TH 17 pathway such as ustekinumab, secukinumab could also be applicable in the process. This review summarizes the detailed CSF findings in NBD, current understanding of the immunopathogenesis of NBD, and treatment of NBD with specific biologic agents based on our understanding of the disease pathogenesis.

Rheumatoid arthritis (RA) is the most common inflammatory rheumatic disease of unknown etiology, determined by the destruction of articular cartilage and bone loss. The hallmark of RA is a defect in immune tolerance. Regulatory T cells (Treg) play a critical role in the protection of peripheral tolerance.

To assess the percentage of Treg CD4+/CD25+/high/CD127low/- cells in peripheral blood of RA patients as compared with the healthy individuals.

The number of Treg CD4+/CD25+/high/CD127low/- cells was assessed by multicolor flow cytometry. The clinical disease activity of RA patients was determined by disease activity score 28 (DAS-28). The correlation of DAS-28 and erythrocyte sedimentation rate (ESR) was evaluated along with Treg cells in peripheral blood of RA patients.

The percentage of Treg CD4+/CD25+/high/CD127low/- cells in peripheral blood of RA patients significantly decreased as compared with the healthy individuals (P= 0.0002). The percentage of Treg CD4+/CD25+/high/CD127low/- cells negatively correlated with DAS-28 and ESR.

This study concludes that the defect of Treg cells plays a vital role in the pathogenesis of this disease. Further studies are necessary to determine the role of Treg cells in the clinical course of rheumatoid arthritis.

Group 2 innate lymphoid cells (ILC2s) promote allergic inflammation by producing interleukin-5 (IL-5), interleukin-13 (IL-13), some interleukin-4 (IL-4) and interleukin-9 (IL-9). Interleukin-18 (IL-18) can promote T helper 2 cell (Th2) response by inducing IL-4 and IL-13 production from mast cells and basophils. However, the regulation of IL-18 on ILC2s is not clear.

Twenty allergic rhinitis (AR) patients and 20 controls were enrolled. The mRNA and protein levels of IL-18 in serum, the frequencies of ILC2 in peripheral blood mononuclear cells (PBMCs) were measured by real-time polymerase chain reaction (PCR), enzyme-linked immunosorbnent assay (ELISA) and flow cytometry. The ILC2s were sorted and the mRNA expression of IL-18 receptor on ILC2 was analyzed by real-time PCR. The effects of IL-18 on the proliferation and type 2 cytokine production were detected by tritiated thymidine incorporation test, real-time PCR and ELISA, respectively.

The levels of IL-18 mRNA and protein were significantly higher in AR patients compared with controls (p <0.05). The proportion of ILC2 in peripheral blood was elevated in AR compared with controls. After stimulation by IL-18 and house dust mite (HDM), the expression of IL-18 receptor (IL-18R) by ILC2 was significantly up-regulated. The tritiated thymidine incorporation results showed that IL-18 promoted the proliferation of ILC2 in a dose dependent manner. IL-18 also induced protein expression of IL-5 and IL-13 by ILC2.

Our results for the first time confirmed the effect of IL-18 in innate immunity, which is proved by direct effect on the differentiation and function of ILC2.

Allergic asthma is believed to be a T helper 2 cell (Th2) preponderant response caused by airway hyper-responsiveness. Interleukin-35 (IL-35) is a newly discovered anti-inflammatory cytokine.

To determine if the expression of IL-35 is associated with type-2 inflammation in children with asthma exacerbations.

Thirty children (6-12 years old) with acute allergic asthma and twenty healthy controls were enrolled. Sputum was induced from lower airways. IL-35 and type 2 cytokines expression from serum and induced sputum were measured at mRNA and protein level by real-time PCR and enzyme-linked immunosorbent assay (ELISA). The sampling and the test were repeated eight weeks after the asthma exacerbation.

At the time of exacerbation, IL-35 expression in induced sputum and serum decreased significantly than in the controls. The expression of IL-35 was negatively correlated with IL-4, IL-5 and IL-13 expression. The IL-35 from induced sputum increased significantly, whereas type-2 cytokines decreased significantly eight weeks after the exacerbation.

Our results showed that decreased IL-35 was associated with type-2 cytokines in asthma exacerbations in children, suggesting that IL-35 may be a potential future drug target for asthma exacerbations.

Acne is a common and chronic inflammatory dermatosis of human hair follicle sebaceous gland units. Acne is closely related to immune cytokines and cells including T reg cells (Th17 cells). Mis-regulated glycolipid metabolism also has a vital role to play in the process.

This investigation aims to explore the role of IL-17 in signaling pathways controlling sebaceous gland lipoprotein metabolism in rat model of acne.

We have performed experimental studies, generated the rat ear acne model, and have investigated the pathological changes of acne skin tissue by histological analysis and the changes of critical factors including DEFB1, GPR65, FADS1, and FADS2 by Western Blot in acne rat model.

There were more Th17 cells in the rat ear acne model than in the control mice. The expression levels of DEFB1, GPR65, FADS1, FADS2 and MOGAT1 were significantly upregulated in serum and tissue from rat acne models, which indicated that Th17 cells play a major role in the occurrence of acne based on the IL-17 signal pathway.

Although acne is associated with immune effects and glycolipid metabolism, inhibition of IL-17 signaling pathway might be a novel way for acne therapy. Our findings also suggest a new target therapy strategy for acne.

Pulmonary manifestations of systemic lupus erythematosus (SLE) are appearing in 4-5% of patients involving lung in almost half of the cases during the disease course.

We compared the autoimmune pulmonary inflammation in the lung tissue of mice to determine the association between the decreased expression levels of Forkhead Box J1 (FOXJ1) and the activation of the NF-κB pathway in autoimmune pulmonary inflammation of MRL/Lpr mice.

The female BALB/c mice (n=6) and MRL/Lpr mice (n=30) were divided into 5 groups including: a control group (BALB/c), and five MRL/Lpr mice groups (8W, 12W, 16W, 24W, and 32W). The inflammation of the inflammatory cells was determined in lung tissue by the histological analysis. The western blotting was used to examine the expression levels of the age-related FOXJ1, and p50 and p65 proteins in the lungs of MRL/Lpr mice. The expression levels of MMP2 and MMP9 were determined via immunohistochemistry and immunofluorescence.

There were severe infiltrates of lung cells with high levels of tracheal damage, perivascular injury and interstitial inflammatory cell infiltration when the MRL/Lpr mice ranged in age from 16w to 32w than in the healthy MRL/Lpr mice in the control group which were at the age of 8w (p<0.05). Moreover, the reduced expression levels of FOXJ1 were associated with the activation of the NF-κB pathway in interstitial lung disease of MRL/Lpr mice via the modulation of p50 and p65. In addition, the expression levels of MMP2 and MMP9 pro-inflammation factors increased in the lungs of the MRL/Lpr mice as they ranged in age from 16w to 32w.

The level of FOXJ1 expression might be a hint at the degree of lung disease in lupus-prone mice.

Primary Eosinophilic Colitis (PEC) is one of the eosinophilic gastrointestinal diseases which is a rare entity with a poorly understood pathogenesis. Eosinophilic esophagitis (EE) is the most common and best-understood disease in this category. Stimulated mast cells (MCs) have a role to play in the tissue damage in EE. It is not known if PEC shares this mechanism.

This cross-sectional study aimed to investigate the number of MCs in PEC and to compare them with cases of secondary colonic tissue eosinophilia (TE) and normal controls.

The study included 19 PEC cases, 47 cases of secondary tissue eosinophilia and 50 normal controls. Histopathological slides of all cases were reviewed to confirm the diagnosis and count the numbers of eosinophils. Glass slides for all cases were stained with a C-kit (CD117) stain to highlight and count the MCs.

The mean number of the MCs in normal controls was 9.7 MCs per HPF (SD= 4.6). The mean number of MCs in the PEC cases was 26.5 (SD=7.1) which is significantly higher than the normal counts (p-value <0.000). The mean number of MCs in the secondary TE group was 18.0 (SD=7.1), which is significantly higher than normal controls; p-value <0.000. Comparing MC counts among PEC and secondary TE also revealed a significant difference with a p-value of < 0.000.

MCs in PEC are significantly higher than those in secondary TE and normal controls. This suggests the role of the MCs in Primary Eosinophilic Colitis pathogenesis.

Systemic lupus erythematous (SLE) is a multisystem autoimmune immune disorder. While the pathogenesis of SLE is so popular, both infectious and non-infectious elements are regarded to exert an important impact on the disease's development.

To explore the overall status of EBV, TLR7, TLR9, and IFN-α gene expression in 32 patients suffering from SLE and 32 healthy controls.

Plasma and PBMCs were separated from fresh whole blood. To measure EBV DNA load and mRNA levels of IFN-a, TLR-7,9 in PBMCs, molecular techniques were employed. The production of IFN-α, ds-DNA IgG antibody, and EBNA-1 IgG levels were also measured in plasma.

SLE patients showed significantly higher EBV load (p=0.001) and transcriptional levels of TLR7 (p=0.0001), IFN-α (p=0.0001), and TLR9 (p=0.0001) than in the controls. Moreover, the plasma levels of IFN-α (p=0.0002) and EBNA-1specific IgG antibody (p=0.01) were significantly higher in SLE patients.

The results stressed the potential role of EBV infection and TLRs in SLE patients although more research is needed to determine the global impact that EBV infection can have on immune signature in patients with SLE.

Changes in the expression of cytokines as the result of the single nucleotide polymorphisms (SNPs), can affect the occurrence of multiple sclerosis (MS).

To investigate the frequency of interleukin-10 (IL-10)-1082 A/G (rs1800896) and the CCR5-delta32 genotypes on susceptibility to MS in the Iranian Azari population.

IL-10-1082 A/G SNP and the CCR5-delta32 in 152 patients suffering from MS and 242 healthy non-relatives were genotyped by allele specific-PCR and simple PCR methods, respectively.

The frequencies of AA (37.6%) and AG (55.9%) genotypes of IL-10-1082 were significantly high in the control (p = 0.021) and MS patients (p = 0.015), respectively, with no statistical difference. There was no significant difference in the CCR5 gene based on the possession of wild/wild and wild/del32 genotypes between MS patients and the control group. The del32/del32 genotype was not seen in any of the investigated groups. Tobacco (cigarettes and hookahs) consumption was higher among the MS patients (p=0.004), and this has the potential to raise the risk of MS in both the individuals and their families. It had no significant relation with the frequency of different genotypes of the IL-10-1082 and the CCR5. MS disease was more prevalent among people with low-income. (p=0.0001).

Our finding concludes on possible role of AA genotype of IL-10 -1082 as a protective factor in studied patients.

Rheumatoid arthritis (RA) is a complex systemic autoimmune disorder with multifactorial nature. Numerous previous studies have shown that several genes are involved in the pathogenesis and have increased the risk of RA. The Nod-like receptor pyrin domain containing 3 (NLRP3) involved in the regulation of innate immunity which its upregulation in RA have previously been reported.

To evaluate any correlation between 3 functional polymorphisms of NLRP3 and its gene expression and subsequently to RA risk.

One hundred and fourteen patients with RA and 120 healthy participants were recruited in this case-control study. Genotyping of rs4612666 (intronic variant), rs10754558 (3'UTR variant), and rs6672995 (downstream variant) were performed applying the real-time polymerase chain reaction high-resolution melting (HRM) method.

Based on logistic regression analysis, subjects with CC genotype and C allele in rs4612666 had increased the risk of RA (OR for CC genotype= 3.10; 95%CI [1.78-8.26]/ OR for C allele= 2.00; 95%CI [1.45-3.10]). Furthermore, in the patient groups, there was a significant relationship between the concentration of C-reactive protein (CRP) with rs4612666 and rs10754558 polymorphism (P< 0.05). Besides, our results revealed no important association between the genotype and allele frequency of rs10754558 and rs6672995 with the risk of RA (P> 0.05).

Our findings propose a considerable association between rs4612666 polymorphism and a rise of the risk of RA. Moreover, rs4612666 and rs10754558 were correlated with disease activity in the Iranian population.

Purpuric nephritis is the most common secondary glomerular disease in childhood. Its prevalence in children has been steadily rising in recent years.

To explore the characteristics and pathogenesis of peripheral blood lymphocyte subsets and immune function changes in children with Henoch-Schonlein purpura nephritis.

The study included 104 children with Henoch-Schonlein purpura, divided into nephritis (HSPN) group (68 cases) and non-nephritis (NHSPN) group (36 cases), and 15 normal children were included as the control group. The rate-scatter turbidimetric method was utilized to determine the immunoglobulins IgA, IgG, IgM, C3 and C4, and the flow cytometry analysis technique was employed to detect the levels of lymphocyte subsets such as CD3+, CD4+, CD8+, CD4+/CD8+, CD19+, NK, etc.

Compared with the control group, the CD3+, CD4+, CD8+ and NK cell levels of peripheral blood mononuclear cells in the HSPN group and the NHSPN group significantly decreased (P<0.05), and the CD19+ level significantly elevated (P<0.05); whereas the HSPN group had a more significant change than the NHSPN group (P<0.05). Compared with the control group, the serum immunoglobulin IgA and IgG of the HSPN group and the NHSPN group significantly increased, and the IgM, C3, and C4 significantly decreased (P<0.05); while the HSPN group had a more significant change than the NHSPN group (P<0.05).

Immune dysfunction in children with HSPN is specifically manifested as low cellular immune function, which leads to an increased secretion of inflammatory mediators, activates B cells, and further increases the secretion of immunoglobulins, leading to the occurrence of small vasculitis.