Immunological insights: assessing immune parameters in medical professionals exposed to SARS-CoV-2.

BACKGROUND: The immunological background responsible for the severe course of COVID-19 and the immune factors that protect against SARS-CoV-2 infection are still unclear. The aim of this study was to investigate immune system status in persons with high exposure to SARS-CoV-2 infection. METHODS: Seventy-one persons employed in the observation and infectious diseases unit were qualified for the study between November 2020 and October 2021. Symptomatic COVID-19 was diagnosed in 35 persons. Anti-SARS-CoV-2 antibodies were also found in 8 persons. Peripheral blood mononuclear cells subpopulations were analyzed by flow cytometry, and the concentrations of cytokines and anti-SARS-CoV-2 antibodies were determined by ELISA. RESULTS: The percentages of cytotoxic T lymphocytes (CTLs), CD28+ and T helper (Th) cells with invariant T-cell receptors were significantly higher in persons with symptomatic COVID-19 than in those who did not develop COVID-19' symptoms. Conversely, symptomatic COVID-19 persons had significantly lower percentages of: a) CTLs in the late stage of activation (CD8+/CD95+), b) NK cells, c) regulatory-like Th cells (CD4+/CTLA-4+), and d) Th17-like cells (CD4+/CD161+) compared to asymptomatic COVID-19' persons. Additionally, persons with anti-SARS-CoV-2 antibodies had a significantly higher lymphocyte count and IL-6 concentration than persons without these antibodies. CONCLUSION: Numerous lymphocyte populations are permanently altered by SARS-CoV-2 infection. High percentages of both populations: NK cells-as a part of the non-specific response, and T helper cells' as those regulating the immune response, could protect against the acute COVID-19 symptoms development. Understanding the immune background of COVID-19 may improve the prevention of this disease by identifying people at risk of a severe course of infection. TRIAL REGISTRATION: This is a retrospective observational study without a trial registration number.

Alloreactive memory CD4 T cells promote transplant rejection by engaging DCs to induce innate inflammation and CD8 T cell priming.

Alloreactive memory T cells have been implicated as central drivers of transplant rejection. Perplexingly, innate cytokines, such as IL-6, IL-1ß, and IL-12, are also associated with rejection of organ transplants. However, the pathways of innate immune activation in allogeneic transplantation are unclear. While the role of microbial and cell death products has been previously described, we identified alloreactive memory CD4 T cells as the primary triggers of innate inflammation. Memory CD4 T cells engaged MHC II-mismatched dendritic cells (DCs), leading to the production of innate inflammatory cytokines. This innate inflammation was independent of several pattern recognition receptors and was primarily driven by TNF superfamily ligands expressed by alloreactive memory CD4 T cells. Blocking of CD40L and TNFα resulted in dampened inflammation, and mice genetically deficient in these molecules exhibited prolonged survival of cardiac allografts. Furthermore, myeloid cell and CD8 T cell infiltration into cardiac transplants was compromised in both CD40L- and TNFα-deficient recipients. Strikingly, we found that priming of naive alloreactive CD8 T cells was dependent on licensing of DCs by memory CD4 T cells. This study unravels the key mechanisms by which alloreactive memory CD4 T cells contribute to destructive pathology and transplant rejection.

Varicella Zoster Virus disrupts MAIT cell polyfunctional effector responses.

Mucosal-associated invariant T (MAIT) cells are unconventional T cells that respond to riboflavin biosynthesis and cytokines through TCR-dependent and -independent pathways, respectively. MAIT cell activation plays an immunoprotective role against several pathogens, however the functional capacity of MAIT cells following direct infection or exposure to infectious agents remains poorly defined. We investigated the impact of Varicella Zoster Virus (VZV) on blood-derived MAIT cells and report virus-mediated impairment of activation, cytokine production, and altered transcription factor expression by VZV infected (antigen+) and VZV exposed (antigen-) MAIT cells in response to TCR-dependent and -independent stimulation. Furthermore, we reveal that suppression of VZV exposed (antigen-) MAIT cells is not mediated by a soluble factor from neighbouring VZV infected (antigen+) MAIT cells. Finally, we demonstrate that VZV impairs the cytolytic potential of MAIT cells in response to riboflavin synthesising bacteria. In summary, we report a virus-mediated immune-evasion strategy that disarms MAIT cell responses.

Introduction.

The coronavirus disease 2019 (COVID-19) pandemic emerged just months after the publication of the first ever textbook devoted to cytokine storm syndromes (CSSs). The severe disease caused by COVID-19 and the intersection between immune responses and their pathologies played out before the world in media reports, in scientific publications, and through the personal narratives of millions of people's experiences. An entirely new immune-mediated disease, multisystem inflammatory disease in children (MISC), was described. Cytokines played a role in all of these areas, bringing the idea of a cytokine storm squarely to the front and center of the public eye. At the same time, science continued to progress in the lab and in the clinic, thus illuminating our understanding of CSSs both old and new since the publication of the first edition of this book. It was clear that a new edition was needed to keep up with these changes.

Cytokines in Cytokine Storm Syndrome.

As the eponymous mediators of the cytokine storm syndrome, cytokines are a pleomorphic and diverse set of soluble molecules that activate or suppress immune functions in a wide variety of ways. The relevant cytokines for each CSS are likely a result of differing combinations of environmental triggers and host susceptibilities. Because cytokines or their receptors may be specifically targeted by biologic therapeutics, understanding which cytokines are relevant for disease initiation and propagation for each unique CSS is of major clinical importance. This chapter will review what is known about the role of cytokines across the spectrum of CSS.

Monocytic Phagocytes in the Immunopathogenesis of Cytokine Storm Syndromes.

Cytokine storm syndromes (CSSs) are caused by a dysregulated host immune response to an inciting systemic inflammatory trigger. This maladaptive and harmful immune response culminates in collateral damage to host tissues resulting in life-threatening multisystem organ failure. Knowledge of the various immune cells that contribute to CSS pathogenesis has improved dramatically in the past decade. Monocytes, dendritic cells, and macrophages, collective known as monocytic phagocytes, are well-positioned within the immune system hierarchy to make key contributions to the initiation, propagation, and amplification of the hyperinflammatory response in CSS. The plasticity of monocytic phagocytes also makes them prime candidates for mediating immunoregulatory and tissue-healing functions in patients who recover from cytokine storm-mediated immunopathology. Therefore, approaches to manipulate the myriad functions of monocytic phagocytes may improve the clinical outcome of CSS.

Cytokine Storm Syndromes Associated with Epstein-Barr Virus.

Epstein-Barr virus (EBV) is a ubiquitous and predominantly B cell tropic virus. One of the most common viruses to infect humans, EBV, is best known as the causative agent of infectious mononucleosis (IM). Although most people experience asymptomatic infection, EBV is a potent immune stimulus and as such it elicits robust proliferation and activation of the B-lymphocytes it infects as well as the immune cells that respond to infection. In certain individuals, such as those with inherited or acquired defects affecting the immune system, failure to properly control EBV leads to the accumulation of EBV-infected B cells and EBV-reactive immune cells, which together contribute to the development of often life-threatening cytokine storm syndromes (CSS). Here, we review the normal immune response to EBV and discuss several CSS associated with EBV, such as chronic active EBV infection, hemophagocytic lymphohistiocytosis, and post-transplant lymphoproliferative disorder. Given the critical role for cytokines in driving inflammation and contributing to disease pathogenesis, we also discuss how targeting specific cytokines provides a rational and potentially less toxic treatment for EBV-driven CSS.

Inborn Errors of Immunity and Cytokine Storm Syndromes.

Inborn errors of immunity (IEI) are a diverse and growing category of more than 430 chronic disorders that share susceptibilities to infections. Whether the result of a genetic lesion that causes defective granule-dependent cytotoxicity, excessive lymphoproliferation, or an overwhelming infection represents a unique antigenic challenge, IEIs can display a proclivity for cytokine storm syndrome (CSS) development. This chapter provides an overview of CSS pathophysiology as it relates to IEIs. For each IEI, the immunologic defect and how it promotes or discourages CSS phenomena are reviewed. The IEI-associated molecular defects in pathways that are postulated to be critical to CSS physiology (i.e., toll-like receptors, T regulatory cells, the IL-12/IFNγ axis, IL-6) and, whenever possible, review strategies for treating CSS in IEI patients with molecularly directed therapies are highlighted.

COVID-19 Pneumonia and Cytokine Storm Syndrome.

Virus-associated cytokine storm syndrome (CSS) has been recognized for a long time and the classic viruses associated are the herpes viruses EBV, CMV, and HHV-8 as described in chapters IVa,b. In addition, pandemic viruses such as influenza, SARS, and MERS can result in severe CSS that might ultimately lead to severe acute respiratory distress syndrome (ARDS) and death [1-3]. A new pandemic caused by SARS-CoV-2 that started in 2019 has defined another chapter in the virus-associated CSS. The clinical spectrum of SARS-CoV-2 infection has many faces. In most people, it will be asymptomatic, but it can also result in severe COVID-19 pneumonia, ARDS, and multiorgan failure depending on age, comorbidities, and immune status [4]. In addition, this pandemic has known many different stages and developed in a unique way in the first 2 years. It started in a setting where there was no immunity to the virus and after a year, highly effective vaccines were introduced and herd immunity built up over time. However, vaccine effectiveness was waning over time depending on multiple factors, and novel variant strains of the virus circulated across different areas in the world. Antiviral therapy was developed and introduced, and treatment changed from giving no immunomodulatory treatment, followed by the introduction of corticosteroids [5], and later the addition of more targeted strategies such as JAK inhibitors [6] and blocking IL-6 signaling [7]. Therefore, the scientific literature published on COVID-19 must be seen in the context of a highly dynamic and rapidly changing pandemic, making it difficult to compare results from early studies to more recent reports even within 2 years. Still, a lot has been learned over a very short period. It has become apparent that severe COVID-19 is predominantly a disease of immune dysregulation with components that can be defined as CSS. It has unique features and overlapping characteristics with other CSSs, and immunological treatment addressing the CSS has been extensively explored, which will be described here.

Autoinflammatory Contributors to Cytokine Storm.

Cytokine Storm is a complex and heterogeneous state of life-threatening systemic inflammation and immunopathology. Autoinflammation is a mechanistic category of immune dysregulation wherein immunopathology originates due to poor regulation of innate immunity. The growing family of monogenic Systemic Autoinflammatory Diseases (SAIDs) has been a wellspring for pathogenic insights and proof-of-principle targeted therapeutic interventions. There is surprisingly little overlap between SAID and Cytokine Storm Syndromes, and there is a great deal to be inferred from those SAID that do, and do not, consistently lead to Cytokine Storm. This chapter will summarize how illustrations of the autoinflammatory paradigm have advanced the understanding of human inflammation, including the role of autoinflammation in familial HLH. Next, it will draw from monogenic SAID, both those with strong associations with cytokine storm and those without, to illustrate how the cytokine IL-18 links innate immune dysregulation and cytokine storm.

Multimodal mucosal and systemic immune characterization of a non-human primate trachoma model highlights the critical role of local immunity during acute phase disease.

BACKGROUND: Trachoma is a leading cause of infection-related blindness worldwide. This disease is caused by recurrent Chlamydia trachomatis (Ct) infections of the conjunctiva and develops in two phases: i) active (acute trachoma, characterized by follicular conjunctivitis), then long-term: ii) scarring (chronic trachoma, characterized by conjunctival fibrosis, corneal opacification and eyelid malposition). Scarring trachoma is driven by the number and severity of reinfections. The immune system plays a pivotal role in trachoma including exacerbation of the disease. Hence the immune system may also be key to developing a trachoma vaccine. Therefore, we characterized clinical and local immune response kinetics in a non-human primate model of acute conjunctival Ct infection and disease. METHODOLOGY/PRINCIPAL FINDINGS: The conjunctiva of non-human primate (NHP, Cynomolgus monkeys-Macaca fascicularis-) were inoculated with Ct (B/Tunis-864 strain, B serovar). Clinical ocular monitoring was performed using a standardized photographic grading system, and local immune responses were assessed using multi-parameter flow cytometry of conjunctival cells, tear fluid cytokines, immunoglobulins, and Ct quantification. Clinical findings were similar to those observed during acute trachoma in humans, with the development of typical follicular conjunctivitis from the 4th week post-exposure to the 11th week. Immunologic analysis indicated an early phase influx of T cells in the conjunctiva and elevated interleukins 4, 8, and 5, followed by a late phase monocytic influx accompanied with a decrease in other immune cells, and tear fluid cytokines returning to initial levels. CONCLUSION/SIGNIFICANCE: Our NHP model accurately reproduces the clinical signs of acute trachoma, allowing for an accurate assessment of the local immune responses in infected eyes. A progressive immune response occurred for weeks after exposure to Ct, which subsided into a persistent innate immune response. An understanding of these local responses is the first step towards using the model to assess new vaccine and therapeutic strategies for disease prevention.

Immune and inflammation features of severe and critical Omicron infected patients during Omicron wave in China.

OBJECTIVE: The current study aimed to investigate the baseline immune and inflammatory features and in-hospital outcomes of patients infected with the Omicron variant (PIWO) who presented with different disease severities during the first wave of mass Omicron infections in the Chinese population has occurred. METHOD: A cross-sectional study was conducted on 140 hospitalized PIWO between December 11, 2022, and February 16, 2023. The clinical features, antibodies against SARS-CoV-2, immune cells, and inflammatory cytokines among mildly, severely, and critically ill PIWO at baseline and during follow-up period were compared. RESULT: Patients with severe (n = 49) and critical (n = 35) disease were primarily male, needed invasive mechanical ventilation treatment, and exhibited higher mortality than those with mild disease (n = 56). During acute infection, SARS-CoV-2-specific antibody levels fluctuated with disease severity, serum antibodies increased and the incidence of severe cases decreased in critically ill PIWO over time. Antibody titers in severe or critical PIWO with no antibody responses at baseline did not increase significantly over time. Meanwhile, CD4+T cell, CD8+T cell, and natural killer cell counts were negatively correlated with disease severity, whereas interleukin (IL)-6 and IL-10 levels were positively correlated. In addition, combined diabetes, immunosuppressive therapy before infection, serum amyloid A, IL-10 and neutrophil counts were independently associated with severe and critical illness in PIWO. Among the 11 nonsurvivors, 8, 2, 1 died of respiratory failure, sudden cardiac death, and renal failure, respectively. Compared with survivors, nonsurvivors exhibited lower seropositivity of SARS-CoV-2-specific antibody, reduced CD3+T and CD4+T cell counts, and higher IL-2R, IL-6, IL-8, and IL-10 levels. Of note, lactate dehydrogenase was a significant risk factor of death in severe or critically ill PIWO. CONCLUSION: This present study assessed the dynamic changes of SARS-CoV-2-specific antibodies, immune cells and inflammatory indexes between severely and critically ill PIWO. Critical and dead PIWO featured compromised humoral immune response and excessive inflammation, which broadened the understanding of the pathophysiology of Omicron infection and provides warning markers for severe disease and poor prognosis.

Effect of pseudorabies virus infection on NMDA receptor expression in mice and its role in immunosuppression.

Pseudorabies virus (PRV), an α-herpesvirus, induces immunosuppression and can lead to severe neurological diseases. N-methyl-D-aspartate receptor (NMDAR), an important excitatory nerve receptor in the central nervous system, is linked to various nervous system pathologies. The link between NMDAR and PRV-induced neurological diseases has not been studied. In vivo studies revealed that PRV infection triggers a reduction in hippocampal NMDAR expression, mediated by inflammatory processes. Extensive hippocampal neuronal degeneration was found in mice on the 6th day by hematoxylin-eosin staining, which was strongly correlated with increased NMDAR protein expression. In vitro studies utilizing the CCK-8 assay demonstrated that treatment with an NMDAR antagonist significantly heightened the cytotoxic effects of PRV on T lymphocytes. Notably, NMDAR inhibition did not affect the replication ability of PRV. However, it facilitated the accumulation of pro-inflammatory cytokines in PRV-infected T cells and enhanced the transcription of the CD25 gene through the secretion of interleukin-2 (IL-2), consequently exacerbating immunosuppression. In this study, we found that NMDAR has functional activity in T lymphocytes and is crucial for the inflammatory and immune responses triggered by PRV infection. These discoveries highlight the significant role of NMDAR in PRV-induced neurological disease pathogenesis.

[Research advance on the interaction between gut microbes and cytokines in inflammatory bowel disease].

Dysregulation of interaction between the gut microbiota and the host immune system leads to the development of chronic inflammation, such as inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). Numerous studies have shown that the host-microbiota of IBD can directly or indirectly affect the homeostasis of the immune system. Furthermore, the balance between pro-inflammatory and anti-inflammatory cytokines involves in maintaining a healthy microbiota community and enhances epithelial barrier functions. Understanding the interactions between gut microbiota and cytokines (IL-10, IL-17, IL-18, TNF-α) provides crucial insights into the pathogenesis of inflammatory bowel disease.

[Advances in the study of natural killer (NK) cells' response to Mycobacterium tuberculosis infection].

Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (MTB) infection and poses a serious threat to human health. Natural killer (NK) cells, an important component of innate immunity, can differentiate into various subpopulations in response to MTB infection, showing a diversity of receptors and functions. They engage in crosstalk with other immune cells by secreting cytokines, thereby exerting anti-infective actions against MTB infection and enhancing the body's immune response to the infection.

Age-dependent Powassan virus lethality is linked to glial cell activation and divergent neuroinflammatory cytokine responses in a murine model.

Powassan virus (POWV) is an emergent tick-borne flavivirus that causes fatal encephalitis in the elderly and long-term neurologic sequelae in survivors. How age contributes to severe POWV encephalitis remains an enigma, and no animal models have assessed age-dependent POWV neuropathology. Inoculating C57BL/6 mice with a POWV strain (LI9) currently circulating in Ixodes ticks resulted in age-dependent POWV lethality 10-20 dpi. POWV infection of 50-week-old mice was 82% fatal with lethality sequentially reduced by age to 7.1% in 10-week-old mice. POWV LI9 was neuroinvasive in mice of all ages, causing acute spongiform CNS pathology and reactive gliosis 5-15 dpi that persisted in survivors 30 dpi. High CNS viral loads were found in all mice 10 dpi. However, by 15 dpi, viral loads decreased by 2-4 logs in 10- to 40-week-old mice, while remaining at high levels in 50-week-old mice. Age-dependent differences in CNS viral loads 15 dpi occurred concomitantly with striking changes in CNS cytokine responses. In the CNS of 50-week-old mice, POWV induced Th1-type cytokines (IFNγ, IL-2, IL-12, IL-4, TNFα, IL-6), suggesting a neurodegenerative pro-inflammatory M1 microglial program. By contrast, in 10-week-old mice, POWV-induced Th2-type cytokines (IL-10, TGFß, IL-4) were consistent with a neuroprotective M2 microglial phenotype. These findings correlate age-dependent CNS cytokine responses and viral loads with POWV lethality and suggest potential neuroinflammatory therapeutic targets. Our results establish the age-dependent lethality of POWV in a murine model that mirrors human POWV severity and long-term CNS pathology in the elderly. IMPORTANCE: Powassan virus is an emerging tick-borne flavivirus causing lethal encephalitis in aged individuals. We reveal an age-dependent POWV murine model that mirrors human POWV encephalitis and long-term CNS damage in the elderly. We found that POWV is neuroinvasive and directs reactive gliosis in all age mice, but at acute stages selectively induces pro-inflammatory Th1 cytokine responses in 50-week-old mice and neuroprotective Th2 cytokine responses in 10-week-old mice. Our findings associate CNS viral loads and divergent cytokine responses with age-dependent POWV lethality and survival outcomes. Responses of young mice suggest potential therapeutic targets and approaches for preventing severe POWV encephalitis that may be broadly applicable to other neurodegenerative diseases. Our age-dependent murine POWV model permits analysis of vaccines that prevent POWV lethality, and therapeutics that resolve severe POWV encephalitis.

CD4+ and CD8+ T-cell multi-epitope chimeric protein associated with an MPLA adjuvant induce protective efficacy and long-term immunological memory for the immunoprophylaxis of American Tegumentary Leishmaniasis.

American Tegumentary Leishmaniasis (ATL) is a disease of high severity and incidence in Brazil, in addition to being a worldwide concern in public health. Leishmania amazonensis is one of the etiological agents of ATL, and the inefficiency of control measures, associated with the high toxicity of the treatment and the lack of effective immunoprophylactic strategies, makes the development of vaccines indispensable and imminent. In this light, the present study proposes to elaborate a chimeric protein (rChiP), based on the fusion of multiple epitopes of CD4+/CD8+ T cells, identified in the immunoproteome of the parasites L. amazonensis and L. braziliensis. The designed chimeric protein was tested in the L. amazonensis murine model of infection using the following formulations: 25 µg of the rChiP in saline (rChiP group) and 25 µg of the rChiP plus 25 µg of MPLA-PHAD® (rChiP+MPLA group). After completing immunization, CD4+ and CD8+ T cells, stimulated with SLa-Antigen or rChiP, showed an increased production of nitric oxide and intracytoplasmic pro-inflammatory cytokines, in addition to the generation of central and effector memory T cells. rChiP and rChiP+MPLA formulations were able to promote an effective protection against L. amazonensis infection determined by a reduction in the development of skin lesions and lower parasitic burden. Reduction in the development of skin lesions and lower parasitic burden in the vaccinated groups were associated with an increase of nitrite, CD4+/CD8+IFN-γ+TNF-α+ and CD4+/CD8+CD44highCD62Lhigh/low T cells, IgGTotal, IgG2a, and lower rates of IgG1 and CD4+/CD8+IL-10+. This data suggests that proposed formulations could be considered potential tools to prevent ATL.

Towards an optimized model of food allergy in zebrafish.

BACKGROUND: The prevalence of food allergies is on the rise, posing a significant challenge to public health. Rodents serve as the predominant animal model in food allergy research; yet, the application of rodent models proves to be a laborious and time-consuming endeavor. It is imperative to develop novel in vivo models. METHODS: Ovalbumin (OVA) was administered as the allergen, following the recommended dosage used in other species. During the sensitization phase, a dosage of 0.25 mg per 10 tails per 1 L was administered twice daily, and during the challenge phase, the dosage was increased to 3 times the initial level. The study explored two dimensions of sensitization: the mode of exposure, which can be either continuous or intermittent, and the duration of exposure, which includes 3 days, 5 days, and 7 days. We examined midgut pathological changes, immunoglobulins contents, and mRNA expressions associated to T helper cells (Th) 2 cytokines following exposure. RESULTS: A significant 109.3 % increase in the number of eosinophils was observed in the midgut histopathology following intermittent 5-day OVA exposure, which emerged as the most effective model. OVA exposure increased concentrations of immunoglobulin M (IgM) (105.2 %), IgZ (312.1 %), and IgD (304.3 %) in this model. The mRNA expressions of Th2-related interleukin (IL)-4 and IL-13 were also elevated by 132.8 % and 421.0 %, respectively. CONCLUSION: The intermittent 5-day OVA exposure was suggested to be the best constructed zebrafish food allergy model, which may be a potential tool for research into food allergies.

From cytokines to chemokines: Understanding inflammatory signaling in bacterial meningitis.

Bacterial meningitis is a serious central nervous system (CNS) infection, claiming millions of human lives annually around the globe. The deadly infection involves severe inflammation of the protective sheath of the brain, i.e., meninges, and sometimes also consists of the brain tissue, called meningoencephalitis. Several inflammatory pathways involved in the pathogenesis of meningitis caused by Streptococcus pneumoniae, Neisseria meningitidis, Escherichia coli, Haemophilus influenzae, Mycobacterium tuberculosis, Streptococcus suis, etc. are mentioned in the scientific literature. Many in-vitro and in-vivo analyses have shown that after the disruption of the blood-brain barrier (BBB), these pathogens trigger several inflammatory pathways including Toll-Like Receptor (TLR) signaling in response to Pathogen-Associated Molecular Patterns (PAMPs), Nucleotide oligomerization domain (NOD)-like receptor-mediated signaling, pneumolysin related signaling, NF-κB signaling and many other pathways that lead to pro-inflammatory cascade and subsequent cytokine release including interleukine (IL)-1ß, tumor necrosis factor(TNF)-α, IL-6, IL-8, chemokine (C-X-C motif) ligand 1 (CXCL1) along with other mediators, leading to neuroinflammation. The activation of another protein complex, nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome, also takes place resulting in the maturation and release of IL-1ß and IL-18, hence potentiating neuroinflammation. This review aims to outline the inflammatory signaling pathways associated with the pathogenesis of bacterial meningitis leading to extensive pathological changes in neurons, astrocytes, oligodendrocytes, and other central nervous system cells.

Immunology of Cytokine Storm Syndromes: Natural Killer Cells.

Natural killer (NK) cells are innate immune lymphocytes that rapidly produce cytokines upon activation and kill target cells. NK cells have been of particular interest in primary hemophagocytic lymphohistiocytosis (pHLH) since all of the genetic defects associated with this disorder cause diminished cytotoxic capacity of NK cells and T lymphocytes, and assays of NK cell killing are used clinically for the diagnosis of HLH. Herein, we review human NK cell biology and the significance of alterations in NK cell function in the diagnosis and pathogenesis of HLH.