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In recent years, rapid advances in research methods have made single cell analysis possible. Systemic sclerosis (SSc), a disease characterized by the triad of immune abnormalities, fibrosis, and vasculopathy, has also been the subject of various analyses. To summarize the results of single cell analysis in SSc accumulated to date and to deepen our understanding of SSc. Four databases were used to perform a database search on 23rd June 2023. Assessed Grading of Recommendations Assessment, Development and Evaluation certainty of evidence were performed according to PRISMA guidelines. The analysis was completed on July 2023. 17 studies with 358 SSc patients were included. Three studies used PBMCs, six used skin, nine used lung with SSc-interstitial lung diseases (ILDs), and one used lung with SSc-pulmonary arterial hypertension (PAH). The cells studied included immune cells such as T cells, natural killer cells, monocytes, macrophages, and dendritic cells, as well as endothelial cells, fibroblasts, keratinocytes, alveolar type I cells, basal epithelial cells, smooth muscle cells, mesothelial cells, etc. This systematic review revealed the results of single cell analysis, suggesting that PBMCs, skin, SSc-ILD, and SSc-PAH show activation and dysfunction of cells associated with immune-abnormalities, fibrosis, and vasculopathy, respectively. [ABSTRACT FROM AUTHOR]

Mammalian pregnancy is a curious life phenomenon. Immunologically, the mechanism of pregnancy is difficult to explain because it involves the coexistence of an external foreign body (the embryo) and the host (the mother) for a period of time. How did mammals acquire the ability to become pregnant in parallel with altered immunity? Sex in the evolution of life and its impact on anthropology are major topics of discussion. In this paper, we outline (1) sex and evolution in mammals after the advent of our direct ancestors (apes) up to humans (i.e., the Cenozoic Quaternary), including anthropological aspects such as the development of the central nervous system; (2) the development of reproductive immunity during the Paleozoic era, when biodiversity developed explosively (and many sexually reproducing organisms have emerged); and (3) the characteristic reproductive strategies of mammals, including humans with the immunological aspects of viviparity. We present an overview of mammalian reproductive immunity, which is a heretical aspect of immunology. [ABSTRACT FROM AUTHOR]

Infections with parasites, especially those involving nematodes that invade tissues, induce a strong Th2-type immune response, which increases immunoglobulin E and eosinophil levels in the blood and tissues. Eosinophils are not effective against all possible helminth infections, but are known to be effective against nematode larvae. In particular, when a host is re-infected by a species of nematode that it previously encountered, the activation of acquired immunity causes robust accumulation and activation of eosinophils that damages the nematode larvae. Eosinophil production and activation processes are mainly induced by interleukin (IL)-5, which is produced by Th2 cells and group 2 innate lymphoid cells, and eosinophils have been shown to generally participate in host defense, inflammation, and immunomodulation. Recently, several papers have reported host defense by non-antigen-specific immune activation, in which group 2 innate lymphoid cells and Th2 cells produce interleukin (IL)-5 and IL-13 in response to IL-33 stimulation. This immune activation is produced by migrating larvae of a species that differs from the species previously encountered. Eosinophils also play an important role in the eradication of migrating larvae. Thus, eosinophils contribute to host defense in both antigen-specific and non-antigen-specific manners. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is the most common inflammatory skin disease driven by both terminal keratinocyte differentiation defects and type 2 immune responses, and this condition causes psychological and social morbidity. Although patients with severe AD require systemic immunotherapy, conventional agents including ciclosporin could not be used for several years due to side effects such as nephrotoxicity, hypertension and long-term risks of malignancy. It is well known that dupilumab, which blocks receptor binding of both IL-4 and IL-13, is remarkably efficacious in the treatment of AD. We have entered a new era when many novel topical and systemic agents that may have great potential in AD treatment are emerging through clinical trials. The purpose of this article is to summarize the efficacy and safety of the current topical and systemic therapies in AD by reviewing recently published papers regarding phase II/III clinical trials. It is revealed that topical phosphodiesterase 4 inhibitors and Janus kinase (JAK) inhibitors are promising treatments for AD. Moreover, systemic therapies such as biologics targeting IL-13 and oral JAK inhibitors show strong efficacy in AD. [ABSTRACT FROM AUTHOR]

Mixed connective tissue disease (MCTD) is an autoimmune disorder characterized by a combination of clinical features from systemic lupus erythematosus, systemic sclerosis, and inflammatory muscle disease, along with the presence of positive anti-U1-ribonucleoprotein (U1-RNP) antibodies. The exact etiology of the disease remains unclear, but it is believed to involve vascular damage within the context of heightened autoimmune responses. Consequently, Raynaud's phenomenon and pulmonary arterial hypertension are observed in patients with MCTD. While specific biomarkers for MCTD have not yet been identified, the recent study of the utility of anti-survival motor neuron complex (SMN) antibodies in MCTD suggests a promising avenue for further research and the accumulation of additional evidence. [ABSTRACT FROM AUTHOR]

Small bowel adenocarcinoma (SBA) is a rare tumor with an unfavorable prognosis, and due to its rarity, few studies on its treatment are available. Chemotherapy remains the standard of treatment in advanced disease. Recently immunotherapy has demonstrated to be a valid therapeutic option for many solid tumors. We reviewed the data published in literature to understand the impact of immunotherapy in this cancer. [ABSTRACT FROM AUTHOR]

Osteoclasts, derived from the monocyte/macrophage line of bone marrow hematopoietic stem cell progenitors, are the sole bone-resorbing cells of the body. Conventional osteoclast differentiation requires macrophage colony-stimulating factor and receptor activator of nuclear factor kappa-B ligand (RANKL) signaling. Rheumatoid arthritis (RA) is the most prevalent systemic autoimmune disease and inflammatory arthritis characterized by bone destruction. Increased levels of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), in the serum and joints, cause excessive bone destruction. We have recently reported that stimulation of human peripheral blood monocytes with TNF-α and IL-6 induces the differentiation of osteoclasts with bone resorption activity. This review presents the functional differences between representative osteoclasts, conventional RANKL-induced osteoclasts, and recently identified proinflammatory cytokine (TNF-α and IL-6)-induced osteoclasts in RA patients. We believe novel pathological osteoclasts associated with RA will be identified, and new therapeutic strategies will be developed to target these osteoclasts and prevent the progression of bone destruction. [ABSTRACT FROM AUTHOR]

Activated phosphatidyl inositol 3-kinase-delta syndrome (APDS) due to gain-of-function variant in the class IA PI3K catalytic subunit p110d (responsible gene: PIK3CD) was described in 2013. The disease is characterized by recurrent airway infections and bronchiectasis. It is associated with hyper-IgM syndrome due to the defect of immunoglobulin class switch recombination and decreased CD27-positive memory B cells. Patients also suffered from immune dysregulations, such as lymphadenopathy, autoimmune cytopenia or enteropathy. T-cell dysfunction due to increased senescence is associated with a decrease in CD4-positive T lymphocytes and CD45RA-positive naive T lymphocytes, along with increased susceptibility to Epstein-Barr virus/cytomegalovirus infections. In 2014, loss-of-function (LOF) mutation of p85a (responsible gene: PIK3R1), a regulatory subunit of p110d, was identified as a causative gene, followed in 2016 by the identification of the LOF mutation of PTEN, which dephosphorylates PIP3, leading to the differentiation of APDS1 (PIK3CD-GOF), APDS2 (PIK3R1-LOF) and APDS-L (PTEN-LOF). Since the pathophysiology of patients with APDS varies with a wide range of severity, it is crucial that patients receive appropriate treatment and management. Our research group created a disease outline and a diagnostic flow chart and summarized clinical information such as the severity classification of APDS and treatment options. [ABSTRACT FROM AUTHOR]

JAK inhibitors are important therapeutic options for hematological disorders, especially myeloproliferative neoplasms. Ruxolitinib, the first JAK inhibitor approved for clinical use, improves splenomegaly and ameliorates constitutional symptoms in both myelofibrosis and polycythemia vera patients. Ruxolitinib is also useful for controlling hematocrit levels in polycythemia vera patients who were inadequately controlled by conventional therapies. Furthermore, pretransplantation use of ruxolitinib may improve the outcome of allo-hematopoietic stem cell transplantation in myelofibrosis. In contrast to these clinical merits, evidence of the disease-modifying action of ruxolitinib, i.e., reduction of malignant clones or improvement of bone marrow pathological findings, is limited, and many myelofibrosis patients discontinued ruxolitinib due to adverse events or disease progression. To overcome these limitations of ruxolitinib, several new types of JAK inhibitors have been developed. Among them, fedratinib was proven to provide clinical merits even in patients who were resistant or intolerant to ruxolitinib. Pacritinib and momelotinib have shown merits for myelofibrosis patients with thrombocytopenia or anemia, respectively. In addition to treatment for myeloproliferative neoplasms, recent studies have demonstrated that JAK inhibitors are novel and attractive therapeutic options for corticosteroid-refractory acute as well as chronic graft versus host disease. [ABSTRACT FROM AUTHOR]

Programmed cell death 1 (PD-1) is an immune checkpoint and has been reported to be associated with several autoimmune diseases. We aimed to investigate the association between human PD-1 gene (PDCD1) polymorphisms and multiple sclerosis (MS). This case-control study was conducted on 229 MS patients and 246 healthy controls. Genotyping of rs36084323 (PD-1.1 G/A), rs11568821 (PD-1.3 G/A) and rs2227981 (PD-1.5 C/T) polymorphisms was performed by PCR-RFLP technique. The frequency difference of PD-1.1 genotypes and alleles (−536 G/A) between patients and healthy controls was not significant. Regarding PD-1.3, the AA + AG genotype was found to be relatively higher in the control group. Concerning PD-1.5 (+7785 C/T), the frequency of T allele carriers (TT + CT) was relatively higher in MS patients, which was marginally insignificant (p =.07). PD-1 gene polymorphisms may be associated with MS; however, accurate conclusions require further studies with a larger number of samples. [ABSTRACT FROM AUTHOR]

CD4+ T lymphocytes play an essential role in adaptive immune responses. In pathogen infection, naïve CD4+ T cells that strongly respond to foreign antigens robustly proliferate to differentiate into effector/memory cells, contributing to elimination of the pathogen concerned. In addition to this conventional T cell activation pathway, naïve T cells can also weakly respond to self antigens in the periphery to spontaneously acquire a memory phenotype through homeostatic proliferation in steady state. Such 'memory-phenotype' (MP) CD4+ T lymphocytes are distinguishable from foreign antigen-specific memory cells in terms of marker expression. Once generated, MP cells are maintained by rapid proliferation while differentiating into the T-bet+ 'MP1' subset, with the latter response promoted by IL-12 homeostatically produced by type 1 dendritic cells. Importantly, MP1 cells possess innate immune function; they can produce IFN-γ in response to IL-12 and IL-18 to contribute to host defense against pathogens. Similarly, the presence of RORγt+ 'MP17' and Gata3hi 'MP2' cells as well as their potential immune functions have been proposed. In this review, I will discuss our current understanding on the unique mechanisms of generation, maintenance, and differentiation of MP CD4+ T lymphocytes as well as their functional significance in various disease conditions. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 virus has become a global health problem that has caused millions of deaths worldwide. The infection can present with multiple clinical features ranging from asymptomatic or mildly symptomatic patients to patients with severe or critical illness that can even lead to death. Although the immune system plays an important role in pathogen control, SARS-CoV-2 can drive dysregulation of this response and trigger severe immunopathology. Exploring the mechanisms of the immune response involved in host defense against SARS-CoV-2 allows us to understand its immunopathogenesis and possibly detect features that can be used as potential therapies to eliminate the virus. The main objective of this review on SARS-CoV-2 is to highlight the interaction between the virus and the immune response. We explore the function and action of the immune system, the expression of molecules at the site of infection that cause hyperinflammation and hypercoagulation disorders, the factors leading to the development of pneumonia and subsequent severe acute respiratory distress syndrome which is the leading cause of death in patients with COVID-19. [ABSTRACT FROM AUTHOR]

Mammalian pregnancy is a curious life phenomenon. Immunologically, the mechanism of pregnancy is difficult to explain because it involves the coexistence of an external foreign body (the embryo) and the host (the mother) for a period of time. How did mammals acquire the ability to become pregnant in parallel with altered immunity? Sex in the evolution of life and its impact on anthropology are major topics of discussion. In this paper, we outline (1) sex and evolution in mammals after the advent of our direct ancestors (apes) up to humans (i.e., the Cenozoic Quaternary), including anthropological aspects such as the development of the central nervous system; (2) the development of reproductive immunity during the Paleozoic era, when biodiversity developed explosively (and many sexually reproducing organisms have emerged); and (3) the characteristic reproductive strategies of mammals, including humans with the immunological aspects of viviparity. We present an overview of mammalian reproductive immunity, which is a heretical aspect of immunology.

Infections with parasites, especially those involving nematodes that invade tissues, induce a strong Th2-type immune response, which increases immunoglobulin E and eosinophil levels in the blood and tissues. Eosinophils are not effective against all possible helminth infections, but are known to be effective against nematode larvae. In particular, when a host is re-infected by a species of nematode that it previously encountered, the activation of acquired immunity causes robust accumulation and activation of eosinophils that damages the nematode larvae. Eosinophil production and activation processes are mainly induced by interleukin (IL)-5, which is produced by Th2 cells and group 2 innate lymphoid cells, and eosinophils have been shown to generally participate in host defense, inflammation, and immunomodulation. Recently, several papers have reported host defense by non-antigen-specific immune activation, in which group 2 innate lymphoid cells and Th2 cells produce interleukin (IL)-5 and IL-13 in response to IL-33 stimulation. This immune activation is produced by migrating larvae of a species that differs from the species previously encountered. Eosinophils also play an important role in the eradication of migrating larvae. Thus, eosinophils contribute to host defense in both antigen-specific and non-antigen-specific manners.

Atopic dermatitis (AD) is the most common inflammatory skin disease driven by both terminal keratinocyte differentiation defects and type 2 immune responses, and this condition causes psychological and social morbidity. Although patients with severe AD require systemic immunotherapy, conventional agents including ciclosporin could not be used for several years due to side effects such as nephrotoxicity, hypertension and long-term risks of malignancy. It is well known that dupilumab, which blocks receptor binding of both IL-4 and IL-13, is remarkably efficacious in the treatment of AD. We have entered a new era when many novel topical and systemic agents that may have great potential in AD treatment are emerging through clinical trials. The purpose of this article is to summarize the efficacy and safety of the current topical and systemic therapies in AD by reviewing recently published papers regarding phase II/III clinical trials. It is revealed that topical phosphodiesterase 4 inhibitors and Janus kinase (JAK) inhibitors are promising treatments for AD. Moreover, systemic therapies such as biologics targeting IL-13 and oral JAK inhibitors show strong efficacy in AD.

Altered abundance and composition of the gut microbiota, i.e., dysbiosis, is reported to be involved in the pathogenesis of various diseases including not only gastrointestinal diseases but also metabolic, neurological, and autoimmune disorders. Fecal microbiota transplantation (FMT) aims to correct dysbiosis by administrating feces collected from donors and thus treat the underlying disease. Ulcerative colitis (UC) is a disease characterized by chronic inflammation in the large intestine. Patients with UC have been reported to have dysbiosis, and more specifically, reduced diversity and abundance of the gut microbiota. FMT has been tried as a treatment for UC. Favorable effects of FMT on UC had been reported in case reports or case series. Recently, four randomized controlled trials of FMT for UC were published. Three of the four studies reported that FMT was more effective than control treatment. Thus, FMT is considered as a promising treatment for UC; however, there are many issues to solve before FMT can become a standard therapy for UC including donor selection, administration routes, frequencies, easy-to-administer formulation development, and optimal patient population. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) involves excessive autoimmune reactions, with pathogenesis characterized by autoantibody production. Although the specific mechanism underlying the development of neuropsychiatric syndromes in SLE (NPSLE) is still unclear, recent studies indicate the involvement of autoimmune pathophysiology. We previously identified the presence of anti-N-methyl-d-aspartate receptor subunit GluN2 antibody (anti-GluN2) as a functional autoantibody which is able to impair neurons and is essential for the diagnosis of diffuse psychiatric/neuropsychological syndromes in NPSLE (dNPSLE). Other autoantibodies like anti-Sm antibodies and anti-glucose-regulated protein 78 antibodies are known to compromise blood brain barrier (BBB) integrity. We demonstrated that high mobility group box-1 protein (HMGB1) decorates synapses on neurons damaged by anti-neuron antibodies, including anti-GluN2, where it behaves as a linker to enhance C1q binding to synapses in a dNPSLE model mouse. This C1q binding via HMGB1 is a critical step for remodeling by activated microglia, which leads to reductions in neuronal complexity and long-term behavioral abnormalities. Suppression of activated microglia can significantly reduce central nervous system (CNS) dysfunction. In this review, we describe the critical steps in the development of dNPSLE in particular, including the phases of BBB breakdown, acute neuronal damage by autoantibodies and neuronal remodeling due to activated microglia. [ABSTRACT FROM AUTHOR]

In rheumatic diseases, advances in biological molecular-targeted therapies have brought remarkable progress in treatment, but the molecular and clinical heterogeneity of the diseases can often pose a treatment challenge. In psoriatic arthritis, each patient exhibits various symptoms, and some may be resistant to treatment. It is difficult to improve all of these various symptoms simultaneously with the use of limited drugs. Therefore, precision medicine is an urgent concern that is required to overcome this problem. However, few studies focus on the precision medicine in rheumatic disease including psoriatic arthritis. We explored the potential of precision medicine in which patients with psoriatic arthritis are stratified by lymphocyte flow cytometry to select specific biologics. Selecting specific biologics according to different immunophenotypes of peripheral blood lymphocytes in psoriatic arthritis was shown to produce high therapeutic responses; in other words, the potential of precision medicine was suggested. The peripheral blood lymphocyte analysis can be applied to many other rheumatic diseases presenting various clinical features, such as spondyloarthritis and systemic lupus erythematous. We should shed light on the precision medicine not only in the psoriatic arthritis also in the other rheumatic disease. [ABSTRACT FROM AUTHOR]

The aim of this study was to find the correlation between severity of dry eye and rheumatoid arthritis (RA) disease activity. Forty- two RA patients with dry eye were recruited from Rheumatology Outpatient Clinic in Minia University Hospital. Assessment of RA disease activity was performed using disease activity score (DAS-28). Ocular tests include Schirmer test I, tear film break up time (TBUT) and ocular staining score (OSS) was performed by ophthalmologist to find evidence of ocular dryness. Erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), anti SSA/Ro and anti SSB/La was also tested. Patients with severe dry (OSS ≥ 3) underwent minor salivary gland biopsy (MSGB) as suspected to have secondary Sjögren's syndrome (SS). Of 42 RA patients, 30 had definite dry eye. DAS-28 did not show significant correlation with any of ocular tests for dryness while the duration of RA was significantly positively correlated with Schirmer test and OSS. The biopsy results of RA patients with severe dry eye show no evidence of SS. The severity of dry eye is not correlated with activity of RA but with its duration. [ABSTRACT FROM AUTHOR]

CD8+T cells are important in protective immunity against intracellular pathogens and tumors. In chronic infections or cancer, CD8+T cells are constantly exposed to antigens and inflammatory signals. Such excessive and constitutive signals lead to the deterioration of T cell function, called 'exhaustion'. Exhausted T cells are characterized by low proliferation in response to antigen stimulation, progressive loss of effector function (cytokine production and killing function), expression of multiple inhibitory receptors such as PD-1, Tim3, and LAG3, and metabolic alterations from oxidative phosphorylation to glycolysis. These dysfunctions are associated with altered transcriptional programs and epigenetic regulations and recent studies suggested that NR4a and TOX transcription factors are deeply involved in exhaustion phenotypes. However, an increase the early memory T cells including stem cell memory T (TSCM) cells is critical for T cell persistence and efficient tumor killing especially for adoptive cancer immunotherapy such as CAR-T cell therapy. An increasing amount of evidence supports the therapeutic potential of targeting exhausted T cells and TSCM cells. We have begun to understand the molecular mechanisms of T cell exhaustion and early memory formation, and the clinical application of converting exhausted T cells to rejuvenated early memory T cells is the goal of our study. [ABSTRACT FROM AUTHOR]

An eight-year-old girl was admitted for prolonged fever and general fatigue. Bilateral reddened and swollen tonsils covered with white fur and increased numbers of atypical lymphocytes in blood led to a diagnosis of infectious mononucleosis (IM) due to primary Epstein–Barr virus (EBV) infection, which was confirmed by a positive anti-EBV viral capsid antigen IgM antibody reaction. She had a swollen thyroid gland and glycosuria at admission, which persisted after IM resolved. Undetectable thyroid-stimulating hormone (TSH), increased thyroid hormone and elevated HbA1c levels led to a diagnosis of autoimmune polyglandular syndrome type3A, based on the presence of antibodies for TSH receptor and glutamic acid decarboxylase. The clinical significance of EBV infection in the development of autoimmune endocrine disorders has been discussed. [ABSTRACT FROM AUTHOR]

Older adults are mostly affected by chronic lymphocytic leukemia (CLL). The present study aimed to evaluate oxidative stress in CLL and to assess its impact on IL-9, Th9 cells levels and prognosis of cases. Seventy Egyptian CLL patients and 15 healthy controls were included. Th9 cell and immunophenotyping of abnormal B cells were assessed by flow cytometry, IL-9 level using ELISA, IL-9 mRNA by qRT-PCR, cytogenetics using FISH, and oxidative stress parameters were determined spectrophotometrically and with native gel electrophoresis. Oxidative stress was elevated in CLL that correlated with abnormal immunophenotyping, cytogenetic changes, bad prognosis, Th9 cells, and overexpression of IL-9. Levels of IL-9 and Th9 cells were strongly correlated with oxidative stress and bad prognostic markers in CLL, indicating that these cells may contribute to CLL by novel mechanisms that could include oxidant injury. [ABSTRACT FROM AUTHOR]

The mortality of colorectal cancer is expected to increase in some countries including the United States, which necessitates the identification of new molecules that help in prognosis assessment and survival improvement. In this brief report, we evaluated the potential of interleukin-34 (IL-34) as a prognostic factor in colorectal cancer. IL-34 was reported for the first time in 2008 as a novel cytokine that controls the biology of the myeloid cell lineage. Accumulating evidence suggests important roles for IL-34 in modifying the tumor microenvironment and enhancing therapeutic resistance of cancer. In this study, we found that IL-34 expression was detectable in various colorectal cancer cell lines in addition to primary cancer tissues from a cohort of Japanese colorectal cancer patients, ranging from high to absent. A Kaplan–Meier analysis showed that high expression of IL-34 correlated with poor survival of colorectal cancer patients. Importantly, in both univariate and multivariate analysis, high IL-34 expression correlated with unfavorable prognosis. A similar relationship between IL-34 expression and the poorer prognosis was also observed in a cohort of colorectal cancer patients registered at The Cancer Genome Atlas. Together, these findings indicate a potential role for IL-34 as a prognostic factor in colorectal cancer. [ABSTRACT FROM AUTHOR]

Intestinal intraepithelial lymphocytes (IELs) are one of the largest populations of lymphocytes and comprised of heterogeneous populations with varying phenotypes and physiological/pathological functions. IELs located between the basolateral surfaces of the epithelial cells and then potentially provide a first line of immune defense against enteric pathogens, although, the precise roles of each IEL populations are not well defined. A variety of molecules are involved in the IEL-homing to the intestinal epithelium. Conventional IELs originate from circulating T cells activated in lymphoid organs and imprinted for gut homing. On the other hand, unconventional IELs derive from thymocytes and migrate to the intestinal epithelium, although, some of them may arise extrathymically. Regarding the interaction between IELs and epithelial cells, IELs are known to be highly motile and actively migrate along the basement membrane, suggesting their roles in immune surveillance. In addition, there has been growing evidence to support that IELs are involved in the pathogenesis of gut disorders such as celiac disease and inflammatory bowel diseases. In this review, we provide a comprehensive overview of IEL dynamics and their clinical significance. [ABSTRACT FROM AUTHOR]