Iranian journal of immunology
Volume:19 Issue: 2, Spring 2022

Follicular helper T (TFH) cells are a subset of effector CD4+ T cells that support the differentiation of antigen-specific B cells in the germinal center. TFH cells are distinct from other established CD4+ T cell subsets and possess a list of transcription factors, including BCL6, IRF4, c-Maf, Batf, NFAT1-2, and STAT3. The mentioned factors direct several activities such as cell differentiation, migration to the follicles, cell-to-cell interaction, as well as cell programming. Given that TFH cells are essential for the germinal center formation, affinity maturation and the development of most high-affinity antibodies. TFH cells may play crucial roles in different pathologic conditions, particularly autoimmune diseases. However, the mechanisms that cause functional differences of TFH cell responses are not exactly defined. In this review first the immunological profile of TFH cells will be discussed then attempts will be made to give a broad picture on the role of this key subset of T cells in autoimmune diseases.

 Several autoimmune and inflammatory disorders, including autoimmune thyroid diseases (AITD), have been linked to Th17 cells and the IL-23/IL-17 axis. Current data suggest that genetic variation contributes greatly to disease susceptibility to AITD.

 To study the role of single nucleotide polymorphisms (SNPs) of IL-23/IL-17 pathway in AITD predisposition and test the gene-gene/gene-sex interactions in these loci.

 A total of 1051 patients with AITD, including 657 patients with Graves' disease (GD) and patients with 394 Hashimoto's thyroiditis (HT), and 874 healthy controls were enrolled in this case-control association study. Six SNPs were selected and genotyped by multiplex PCR combined with high-throughput sequencing. Interactions were tested by the general multifactor dimensionality reduction (GMDR) method.

 Allele C and combinational genotype AC+CC of rs3212227 within il-23 significantly associated with GD with goiter (p=0.003 and 0.014, respectively). Allele G and combinational genotype AG+GG of rs4819554 within il-17ra significantly related to HT with family history and the severity of HT (p=0.011 and 0.027; p=0.041 and 0.035). Also, allele T and genotype CT+TT of rs9463772 within il-17f significantly correlated with the severity of HT (p=0.001 and 0.027, respectively). Moreover, high dimensional gene-sex interaction (il-23r-il-23-il-17ra-il-17f-sex) was identified in AITD, GD, and HT patients with GMDR analysis.

 Our study identified the novel loci and gene-sex interaction in AITD. This evidence, from another perspective, suggests that sex, IL-23/IL-17 pathway, and Th17 cells play an important role in the pathogenesis of AITD.

Vitamin D has anti-inflammatory efficacy against ulcerative colitis (UC), however, the mechanism is yet little understood.

To investigate the immunomodulatory effects of vitamin D against the UC, and to explore the potential downstream mechanisms.

Serum vitamin D, Interferon-γ (IFN-γ) and Interleukin (IL)-17 levels of the patients with UC were quantified using enzyme-linked immunosorbent assay (ELISA). Long non-coding RNAs (lncRNAs) levels were determined by using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Peripheral blood mononuclear cells (PBMCs) were collected from healthy control subjects, stimulated with CD4+ T lymphocytes or helper T cells 17(Th17) differentiation conditions, and then exposed to calcitriol (vitamin D active form) or certain lentiviral treatment, followed by subsequent molecular level testing. For in vivo assay, mice were given 3% dextran sulfate sodium (DSS) to induce colitis.

Compared with the control group, vitamin D levels in the UCs were statistically lower, and there was a negative correlation between IL-17 and vitamin D in the UCs. The lncRNA OIP5-AS1 could decrease under calcitriol treatment in both CD4+ T cells and Th17 differentiation. The lncRNA OIP5-AS1 was a microRNA (miR)-26a-5p sponge and therefore modulated the Th17 cells and IL-6 expression. The lncRNA OIP5-AS1/miR-26a-5p/IL-6 axis mediated the regulation of calcitriol-induced Th17 differentiation. Calcitriol had therapeutic effects on the UC mouse models by regulating the lncRNA OIP5-AS1 related pathway.

Vitamin D might have anti-inflammatory potential in the treatment of the UC.

Pulmonary fibrosis is common in primary Sjögren's syndrome (pSS)-related interstitial lung disease (ILD). However, research is lacking on the diagnostic immunological examination of pSS-related pulmonary fibrosis. Particularly, the value of detecting anti-Ro52 antibody in pulmonary fibrosis is unclear.

To evaluate the potential diagnostic value of anti-SSA, anti-SSB, and anti-Ro52 autoantibodies as markers of pSS-related pulmonary fibrosis.

One-hundred seventy-nine patients with pSS were analyzed retrospectively at our hospital. They were divided into the fibrosis and non-fibrosis groups. Pulmonary fibrosis was classified as mild, moderate, or severe based on the patients' computed tomography (CT) findings. Laboratory examinations, including anti-SSA, anti-SSB, and anti-Ro52 antibody evaluations, were performed. The influencing factors of pulmonary fibrosis were analyzed using logistic regression.

Chest CT revealed pulmonary fibrosis in 45 patients with pSS (25.1%). The positive rates of anti-SSA and anti-Ro52 antibodies in the fibrosis group were lower than in the non-fibrosis group (P=0.04, P=0.001). The frequency of anti-Ro52 antibody showed no significant differences between mild-to-moderate (53.8%) and severe (47.3%) pulmonary fibrosis. The anti-Ro52 antibody was identified as a potentially protective factor against pSS (P=0.041).

Patients with pSS and pulmonary fibrosis had a low frequency of anti-SSA and anti-Ro52 antibodies. In patients with pSS and negative anti-Ro52 antibody, a chest CT is recommended to further understand the patients' condition.

FOXP3, an important transcription factor of regulatory T cells has shown a contribution to the development of various autoimmune diseases.

To investigate the influence of FOXP3 polymorphisms (rs3761548 and rs2294021) on systemic lupus erythematosus (SLE) susceptibility and patients' characteristics.

Genotyping was performed on 265 patients with SLE and 404 healthy controls using PCR-RFLP. Patients' demographic, laboratory, and clinical information were all documented. The relationship between the SNPs and patients' characteristics was statistically analyzed.

The frequency of C/- genotype in male patients was significantly higher than in the healthy male controls, whereas the frequency of A/- genotype was lower (OR=0.53; 95% CI=0.28-1.00, p=.05). Analysis of the correlation between these SNPs and the patients' characteristics showed a longer disease duration in the rs3761548 C/- carriers and a correlation with arthralgia in both SNPs. In the females, there was a significant association between CC haplotype and disease susceptibility (OR=0.6, CI=0.38-0.94, p=.027). A significant association of both SNPs with the history of abortion was also detected. The frequencies of the rs3761548 AA (p=.006) and the rs2294021 CC genotypes (p=.038) and AC/AC combination (p=.033) were higher in women who had an abortion. We found a correlation between the rs3761548 AC genotype and the decreased C4 level and cardiovascular involvement, and the rs2294021 CC genotype with ESR, neurological involvement, and photosensitivity.

FOXP3 rs3761548 C/- genotype association with disease susceptibility in male patients, an association of both SNPs with the abortion risk in female patients, and the correlation between these SNPs and several clinical features of the patients suggest their association with the disease development and pathology.

Concomitant signals from IL-6 and TGF-β have a central role in the Th17 cells development and differentiation, and these cells are the main promoters of demyelinating inflammation in the central nervous system (CNS) resulting in multiple sclerosis (MS).

To evaluate the simultaneous IL-6 and TGF-β gene and their receptor protein expression in patients with Relapsing-Remitting (RR)-MS.

IL-6 and TGF-β mRNA and their receptor expression on the surface of CD4+T cells were evaluated using real-time PCR (RT-PCR) and flow cytometry, respectively.

The IL-6 mRNA expression in patients with RRMS was significantly higher than in the controls (p= 0.019). When patients who did not receive any other treatment were compared with the controls, the significant difference was substantial (p=0.006). The TGF-β mRNA expression in patients was lower than in the controls (p = 0.03). However, in patients receiving IFNβ, it increased compared with the other patients (p= 0.036). There was no difference in cytokine receptor expression between patients and the control group.

Our data conclude an increase and decrease in mRNA expression levels of IL-6 and TGF-β in patients with RRMS, respectively. Moreover, there were no significant differences in receptor expression of either cytokines. Based on our data the balance of TGF and IL-6 appears to have a positive impact on the disease control.

Various factors contribute to the pathogenesis of Multiple Sclerosis (MS), one of which is Fibroblast Growth Factor 2 (FGF2). The function of FGF2 is pleiotropic. The investigation of the role of this factor in the myelination has produced conflicting results.

To investigate the serum levels of FGF2 in patients with MS.

Eighty patients with MS and eighty healthy volunteers with no history of inflammation or demyelinating disorders were included, and serum samples were collected to evaluate serum levels of FGF2 using the ELISA technique. Both groups had the same age and gender distribution. For analysis, the Mann-Whitney U test was used.

Patients with MS had considerably greater serum FGF2 levels than the control group (p = 0.005). There was no difference between the FGF2 level in men and women.

Our data indicate that FGF2 levels may be related to the susceptibility of Iranian patients with MS. Further studies are required to analyze the involvement of FGF2 in enhancing the inflammatory process in MS.

Obesity and diabetes are related to a chronic low-grade inflammation. As a pro-inflammatory cytokine, IL-18 stimulates various cell types and has pleiotropic functions.

To assess the levels of IL-18 in subjects from the entire spectrum of glycemic disorders.

This study included 387 Caucasians divided into four groups: healthy controls, obese subjects without carbohydrate issues, prediabetic patients, and recently discovered type 2 diabetics.

Subject with body mass index ≥30kg/m2 and glycemic disorders showed significantly higher levels of IL-18 (249.77 ± 89.96 pg/ml; 259.01 ± 95.70 pg/ml; and 340.98 ± 127.65 pg/ml) compared with that of the control group (219.47 ± 110.53 pg/ml, p < 0.05). IL-18 also had significant positive associations with some anthropometric parameters, liver enzymes, fasting, post-load glucose, insulin, uric acid, and triglycerides while negative with HDL. The circulating IL-18 levels for differentiating subjects with carbohydrate disturbances and those with metabolic syndrome were determined by ROC analysis. The AUC for the disturbances of the carbohydrate metabolism was 0.597 (p = 0.001; 95% CI = 0.539 - 0.654) and for MS AUC was 0.581 (p = 0.021; 95 % CI = 0.516 - 0.647).

Our data indicate that as the levels of IL-18 are increased the carbohydrate tolerance is deteriorated. However, the significance of IL-18 in the progression of diabetes mellitus and subsequent consequences requires further exploration.

Adult-onset Still's disease (AOSD), which presents many non-specific symptoms, such as rash leukocytosis, spiking fever, and sore throat, is a rare auto inflammatory disease. Other clinical features that are frequently observed include lymphadenopathy, arthralgia, serositis, splenomegaly, and hepatomegaly. Laboratory tests show high levels of C-reactive protein, ferritin, and erythrocyte sedimentation rate reflecting the systemic inflammatory process in AOSD patients.

The patient was a middle-aged woman with a high fever (39.8 C), sore throat, rashes on limbs with pruritus, mainly at the joints (elbow, knee, and ankle), muscle aches, dizziness, infirmity, weakness, and poor appetite without arthralgia. The ferritin level was above 1500 (normal value: 14-233) ng/L. Antineutrophil, antinuclear antibodies, and rheumatoid factor were negative. Combining the symptoms such as fever, rash, stress-induced acute inflammation, arthritis, and ferritin levels, the patient was eventually diagnosed with adult Still's disease. She received methylprednisolone 40mg intravenously every 12 hours for one week. On the second week, the dose was reduced to 40mg in the morning and 20mg in the evening, and finally, the dose was reduced to 40mg oral intake in the morning and 8mg in the evening. After half a month of treatment, the patient's high fever and skin rashes subsided, and the other symptoms also gradually relieved.

A case of a middle-aged woman diagnosed with adult Still's disease is reported, and the possible pathogenesis and treatment of the disease are discussed. This case highlights the importance of early diagnosis and timely treatment of adult Still's disease to prevent potentially fatal complications.

Systemic lupus erythematosus (SLE) is most likely to occur during the first and second trimesters of pregnancy. There were few studies focused on the new-onset SLE during the late pregnancy or puerperium. SLE has been considered an important cause of thrombocytopenia. However, lymphoma may also be a cause of thrombocytopenia. Here, we reported a challenging case of new-onset SLE occurred at the gestational age of 33 weeks, and the pregnant woman suffered lymphoma before.

A 25-year-old primigravid Chinese woman with a medical history of non-Hodgkin lymphoma (NHL) suffered thrombocytopenia at 30+5 weeks of gestation. Her skin rashes occurred one week later. Her platelet count was decreased progressively. She had been misdiagnosed with the recrudescence of NHL. The final diagnosis of new-onset SLE was confirmed and a cesarean section was performed at the 34th week of pregnancy. Both the pregnant woman and the newborn were cured with good prognosis.

SLE should be considered in a pregnant woman with a medical history of malignancy to rule out other diseases, especially the rheumatic immune diseases.