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Current Allergy and Asthma Reports Apr 2023This review focuses on immunologic findings, relationships among immunologic findings and associated conditions of autoimmunity and atopy, and management of immunologic... (Review)
Review
PURPOSE OF REVIEW
This review focuses on immunologic findings, relationships among immunologic findings and associated conditions of autoimmunity and atopy, and management of immunologic disease in chromosome 22q11.2 deletion syndrome (22q11.2DS, historically known as DiGeorge syndrome).
RECENT FINDINGS
The implementation of assessment of T cell receptor excision circles (TRECs) in newborn screening has led to increased detection of 22q11.2 deletion syndrome. While not yet applied in clinical practice, cell-free DNA screening for 22q11.2DS also has the potential to improve early detection, which may benefit prompt evaluation and management. Multiple studies have further elucidated phenotypic features and potential biomarkers associated with immunologic outcomes, including the development of autoimmune disease and atopy. The clinical presentation of 22q11.2DS is highly variable particularly with respect to immunologic manifestations. Time to recovery of immune system abnormalities is not well-defined in current literature. An understanding of the underlying causes of immunologic changes found in 22q11.2DS, and the progression and evolution of immunologic changes over the lifespan have expanded over time and with improved survival. An included case highlights the variability of presentation and potential severity of T cell lymphopenia in partial DiGeorge syndrome and demonstrates successful spontaneous immune reconstitution in partial DiGeorge syndrome despite initial severe T cell lymphopenia.
Topics: Infant, Newborn; Humans; DiGeorge Syndrome; Chromosome Deletion; Neonatal Screening; Lymphopenia; Chromosomes
PubMed: 36897497
DOI: 10.1007/s11882-023-01071-4 -
The New England Journal of Medicine May 2023Idiopathic CD4 lymphocytopenia (ICL) is a clinical syndrome that is defined by CD4 lymphopenia of less than 300 cells per cubic millimeter in the absence of any primary...
BACKGROUND
Idiopathic CD4 lymphocytopenia (ICL) is a clinical syndrome that is defined by CD4 lymphopenia of less than 300 cells per cubic millimeter in the absence of any primary or acquired cause of immunodeficiency. Some 30 years after its original identification, ICL has remained a disease of obscure cause, with limited evidence with respect to its prognosis or management, despite diagnostic and therapeutic innovations.
METHODS
We evaluated the clinical, genetic, immunologic, and prognostic characteristics of 108 patients who were enrolled during an 11-year period. We performed whole-exome and targeted gene sequencing to identify genetic causes of lymphopenia. We also performed longitudinal linear mixed-model analyses of T-cell count trajectories and evaluated predictors of clinical events, the response to immunization against coronavirus disease 2019 (Covid-19), and mortality.
RESULTS
After the exclusion of patients with genetic and acquired causes of CD4 lymphopenia, the study population included 91 patients with ICL during 374 person-years of follow-up. The median CD4+ T-cell count among the patients was 80 cells per cubic millimeter. The most prevalent opportunistic infections were diseases related to human papillomavirus (in 29%), cryptococcosis (in 24%), molluscum contagiosum (in 9%), and nontuberculous mycobacterial diseases (in 5%). A reduced CD4 count (<100 cells per cubic millimeter), as compared with a CD4 count of 101 to 300 cells, was associated with a higher risk of opportunistic infection (odds ratio, 5.3; 95% confidence interval [CI], 2.8 to 10.7) and invasive cancer (odds ratio, 2.1; 95% CI, 1.1 to 4.3) and a lower risk of autoimmunity (odds ratio, 0.5; 95% CI, 0.2 to 0.9). The risk of death was similar to that in the age- and sex-adjusted general population, but the prevalence of cancer was higher.
CONCLUSIONS
Among the study patients, ICL continued to be associated with increased susceptibility to viral, encapsulated fungal, and mycobacterial diseases, as well as with a reduced response to novel antigens and an increased risk of cancer. (Funded by the National Institute of Allergy and Infectious Diseases and the National Cancer Institute; ClinicalTrials.gov number, NCT00867269.).
Topics: Humans; COVID-19; Immunologic Deficiency Syndromes; Lymphopenia; CD4-Positive T-Lymphocytes; CD4 Lymphocyte Count; Opportunistic Infections; Primary Immunodeficiency Diseases
PubMed: 37133586
DOI: 10.1056/NEJMoa2202348 -
International Journal of Molecular... Apr 2021Immune homeostasis is a tightly regulated system that is critical for defense against invasion by foreign pathogens and protection from self-reactivity for the survival... (Review)
Review
Immune homeostasis is a tightly regulated system that is critical for defense against invasion by foreign pathogens and protection from self-reactivity for the survival of an individual. How the defects in this system might result in autoimmunity is discussed in this review. Reduced lymphocyte number, termed lymphopenia, can mediate lymphopenia-induced proliferation (LIP) to maintain peripheral lymphocyte numbers. LIP not only occurs in normal physiological conditions but also correlates with autoimmunity. Of note, lymphopenia is also a typical marker of immune aging, consistent with the fact that not only the autoimmunity increases in the elderly, but also autoimmune diseases (ADs) show characteristics of immune aging. Here, we discuss the types and rates of LIP in normal and autoimmune conditions, as well as the coronavirus disease 2019 in the context of LIP. Importantly, although the causative role of LIP has been demonstrated in the development of type 1 diabetes and rheumatoid arthritis, a two-hit model has suggested that the factors other than lymphopenia are required to mediate the loss of control over homeostasis to result in ADs. Interestingly, these factors may be, if not totally, related to the function/number of regulatory T cells which are key modulators to protect from self-reactivity. In this review, we summarize the important roles of lymphopenia/LIP and the Treg cells in various autoimmune conditions, thereby highlighting them as key therapeutic targets for autoimmunity treatments.
Topics: Animals; Autoimmune Diseases; Autoimmunity; COVID-19; Cell Proliferation; Homeostasis; Humans; Lymphopenia; T-Lymphocytes, Regulatory
PubMed: 33923792
DOI: 10.3390/ijms22084152 -
Nature Reviews. Immunology May 2021Following periods of haematopoietic cell stress, such as after chemotherapy, radiotherapy, infection and transplantation, patient outcomes are linked to the degree of... (Review)
Review
Following periods of haematopoietic cell stress, such as after chemotherapy, radiotherapy, infection and transplantation, patient outcomes are linked to the degree of immune reconstitution, specifically of T cells. Delayed or defective recovery of the T cell pool has significant clinical consequences, including prolonged immunosuppression, poor vaccine responses and increased risks of infections and malignancies. Thus, strategies that restore thymic function and enhance T cell reconstitution can provide considerable benefit to individuals whose immune system has been decimated in various settings. In this Review, we focus on the causes and consequences of impaired adaptive immunity and discuss therapeutic strategies that can recover immune function, with a particular emphasis on approaches that can promote a diverse repertoire of T cells through de novo T cell formation.
Topics: Adaptive Immunity; Animals; B-Lymphocytes; Cellular Microenvironment; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosenescence; Immunotherapy; Lymphopenia; Models, Immunological; Regeneration; Stress, Physiological; T-Lymphocytes
PubMed: 33097917
DOI: 10.1038/s41577-020-00457-z -
Multiple Sclerosis (Houndmills,... Oct 2018In the 2-year CLARITY study, cladribine tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In the 2-year CLARITY study, cladribine tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing-remitting multiple sclerosis (MS).
OBJECTIVE
To assess the safety and efficacy of cladribine treatment in a 2-year Extension study.
METHODS
In this 2-year Extension study, placebo recipients from CLARITY received cladribine 3.5 mg/kg; cladribine recipients were re-randomized 2:1 to cladribine 3.5 mg/kg or placebo, with blind maintained.
RESULTS
A total of 806 patients were assigned to treatment. Adverse event rates were generally similar between groups, but lymphopenia Grade ⩾ 3 rates were higher with cladribine than placebo (Grade 4 lymphopenia occurred infrequently). In patients receiving cladribine 3.5 mg/kg in CLARITY and experiencing lymphopenia Grade ⩾ 3 in the Extension, >90% of those treated with cladribine 3.5 mg/kg and all treated with placebo in the Extension, recovered to Grade 0-1 by study end. Cladribine treatment in CLARITY produced efficacy improvements that were maintained in patients treated with placebo in the Extension; in patients treated with cladribine 3.5 mg/kg in CLARITY, approximately 75% remained relapse-free when given placebo during the Extension.
CONCLUSION
Cladribine tablets treatment for 2 years followed by 2 years' placebo treatment produced durable clinical benefits similar to 4 years of cladribine treatment with a low risk of severe lymphopenia or clinical worsening. No clinical improvement in efficacy was apparent following further treatment with cladribine tablets after the initial 2-year treatment period in this trial setting.
Topics: Adult; Cladribine; Double-Blind Method; Female; Humans; Immunosuppressive Agents; Longitudinal Studies; Lymphopenia; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Treatment Outcome
PubMed: 28870107
DOI: 10.1177/1352458517727603 -
JAMA Internal Medicine Jan 2021Lymphopenia is common and correlates with poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19). (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Lymphopenia is common and correlates with poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19).
OBJECTIVE
To determine whether a therapy that increases peripheral blood leukocyte and lymphocyte cell counts leads to clinical improvement in patients with COVID-19.
DESIGN, SETTING AND PARTICIPANTS
Between February 18 and April 10, 2020, we conducted an open-label, multicenter, randomized clinical trial at 3 participating centers in China. The main eligibility criteria were pneumonia, a blood lymphocyte cell count of 800 per μL (to convert to ×109/L, multiply by 0.001) or lower, and no comorbidities. Severe acute respiratory syndrome coronavirus 2 infection was confirmed with reverse-transcription polymerase chain reaction testing.
EXPOSURES
Usual care alone, or usual care plus 3 doses of recombinant human granulocyte colony-stimulating factor (rhG-CSF, 5 μg/kg, subcutaneously at days 0-2).
MAIN OUTCOMES AND MEASURES
The primary end point was the time from randomization to improvement of at least 1 point on a 7-category disease severity score.
RESULTS
Of 200 participants, 112 (56%) were men and the median (interquartile range [IQR]) age was 45 (40-55) years. There was random assignment of 100 patients (50%) to the rhG-CSF group and 100 (50%) to the usual care group. Time to clinical improvement was similar between groups (rhG-CSF group median of 12 days (IQR, 10-16 days) vs usual care group median of 13 days (IQR, 11-17 days); hazard ratio, 1.28; 95% CI, 0.95-1.71; P = .06). For secondary end points, the proportion of patients progressing to acute respiratory distress syndrome, sepsis, or septic shock was lower in the rhG-CSF group (rhG-CSF group, 2% vs usual care group, 15%; difference, -13%; 95%CI, -21.4% to -5.4%). At 21 days, 2 patients (2%) had died in the rhG-CSF group compared with 10 patients (10%) in the usual care group (hazard ratio, 0.19; 95%CI, 0.04-0.88). At day 5, the lymphocyte cell count was higher in the rhG-CSF group (rhG-CSF group median of 1050/μL vs usual care group median of 620/μL; Hodges-Lehmann estimate of the difference in medians, 440; 95% CI, 380-490). Serious adverse events, such as sepsis or septic shock, respiratory failure, and acute respiratory distress syndrome, occurred in 29 patients (14.5%) in the rhG-CSF group and 42 patients (21%) in the usual care group.
CONCLUSION AND RELEVANCE
In preliminary findings from a randomized clinical trial, rhG-CSF treatment for patients with COVID-19 with lymphopenia but no comorbidities did not accelerate clinical improvement, but the number of patients developing critical illness or dying may have been reduced. Larger studies that include a broader range of patients with COVID-19 should be conducted.
TRIAL REGISTRATION
Chinese Clinical Trial Registry: ChiCTR2000030007.
Topics: Adrenal Cortex Hormones; Adult; Anti-Bacterial Agents; Antiviral Agents; B-Lymphocytes; CD4 Lymphocyte Count; COVID-19; China; Disease Progression; Female; Granulocyte Colony-Stimulating Factor; Hematologic Agents; Hospital Mortality; Humans; Killer Cells, Natural; Leukocyte Count; Lymphocyte Count; Lymphopenia; Male; Middle Aged; Mortality; Noninvasive Ventilation; Oxygen Inhalation Therapy; Recombinant Proteins; Respiratory Distress Syndrome; Respiratory Insufficiency; SARS-CoV-2; Sepsis; Shock, Septic; Time Factors; COVID-19 Drug Treatment
PubMed: 32910179
DOI: 10.1001/jamainternmed.2020.5503 -
FASEB Journal : Official Publication of... Feb 2021Lymphopenia is commonly observed in SARS and COVID-19 patients although the lymphocyte count is not always below 0.8 × 10 /L in all the patients. It is suggested that... (Review)
Review
Lymphopenia is commonly observed in SARS and COVID-19 patients although the lymphocyte count is not always below 0.8 × 10 /L in all the patients. It is suggested that lymphopenia serves as a useful predictor for prognosis in the patients. It is also hypothesized that lymphopenia is related to glucocorticoids and apoptosis. However, the ordering between lymphopenia and apoptosis appears different between SARS and COVID-19 patients, ie, lymphopenia is prior to apoptosis in SARS patients whereas apoptosis is prior to lymphopenia in COVID-19 patients. This paper attempts to figure out this contradiction through three players, lymphopenia, glucocorticoids, and apoptosis. Although the literature does not provide a solid explanation, the level of glucocorticoids could determine the ordering between lymphopenia and apoptosis because the administration of high doses of glucocorticoids could lead to lymphopenia whereas low doses of glucocorticoids could benefit patients. In the meantime, this paper raises several questions, which need to be answered in order to better understand the whole course of COVID-19.
Topics: Apoptosis; COVID-19; Glucocorticoids; Humans; Lymphopenia; Severe acute respiratory syndrome-related coronavirus; SARS-CoV-2; Severe Acute Respiratory Syndrome; COVID-19 Drug Treatment
PubMed: 33495994
DOI: 10.1096/fj.202002512 -
Journal of Leukocyte Biology Jan 2021Bruton's tyrosine kinase (BTK) signaling is involved in innate immune responses and regulates the production of proinflammatory cytokines that can contribute to COVID-19... (Review)
Review
Bruton's tyrosine kinase (BTK) signaling is involved in innate immune responses and regulates the production of proinflammatory cytokines that can contribute to COVID-19 immunopathology. Clinical trials with BTK inhibitors in COVID-19 treatment have been proposed, and previous studies have attempted to investigate the therapeutic effects of ibrutinib and underlying mechanisms in treating viral pneumonia. These attempts, however, did not consider potential off target effect of BTK inhibitors on T cell differentiation, function, and survival, which may be beneficial in treatment for COVID-19. Here, we summarize the current knowledge of BTK/IL-2-inducible T-cell kinase (ITK) signaling in immunopathology and lymphopenia and discuss the potential of BTK/ITK dual inhibitors such as ibrutinib in modulating immunopathology and lymphopenia, for COVID-19 therapy.
Topics: Agammaglobulinaemia Tyrosine Kinase; COVID-19; Cytokines; Humans; Immunity, Innate; Lymphopenia; Protein-Tyrosine Kinases; SARS-CoV-2; Signal Transduction; COVID-19 Drug Treatment
PubMed: 32640487
DOI: 10.1002/JLB.5COVR0620-306R -
The Journal of Allergy and Clinical... Jan 2022Pediatric endogenous Cushing syndrome (eCs) is mainly caused by pituitary corticotropin-producing adenomas, and most glucocorticoid-dependent effects progressively...
BACKGROUND
Pediatric endogenous Cushing syndrome (eCs) is mainly caused by pituitary corticotropin-producing adenomas, and most glucocorticoid-dependent effects progressively regress upon tumor removal. eCs reproduces long-term, high-dose glucocorticoid therapy, representing a clean, natural, and unbiased model in which to study glucocorticoid bona fide effects on immunity.
OBJECTIVE
We performed extensive immunologic studies in otherwise healthy pediatric patients with eCs before and 6 to 13 months after tumor resection, as well as in in vitro glucocorticoid-treated control cells.
METHODS
Flow cytometry, immunoblotting, enzyme-linked immunosorbent assay, real-time quantitative PCR, and RNA-Seq techniques were used to characterize patients' and in vitro glucocorticoid treated cells.
RESULTS
Reduced thymic output, decreased naive T cells, diminished proliferation, and increased T-cell apoptosis were detected before surgery; all these defects eventually normalized after tumor removal in patients. In vitro studies also showed increased T-cell apoptosis, with correspondingly diminished NF-κB signaling and IL-21 levels. In this setting, IL-21 addition upregulated antiapoptotic BCL2 expression and rescued T-cell apoptosis in a PI3K pathway-dependent manner. Similar and reproducible findings were confirmed in eCs patient cells as well.
CONCLUSIONS
We identified decreased thymic output and lymphocyte proliferation, together with increased apoptosis, as the underlying causes to T-cell lymphopenia in eCs patients. IL-21 was decreased in both natural and in vitro long-term, high-dose glucocorticoid environments, and in vitro addition of IL-21 counteracted the proapoptotic effects of glucocorticoid therapy. Thus, our results suggest that administration of IL-21 in patients receiving long-term, high-dose glucocorticoid therapy may contribute to ameliorate lymphopenia and the complications associated to it.
Topics: Adolescent; Apoptosis; Child; Cushing Syndrome; Cytokines; Female; Glucocorticoids; Humans; Leukocyte Count; Lymphopenia; Male; T-Lymphocytes
PubMed: 34089750
DOI: 10.1016/j.jaci.2021.05.031 -
PloS One 2021Lymphopenia is associated with various pathologies such as sepsis, burns, trauma, general anesthesia and major surgeries. All these pathologies are clinically expressed...
BACKGROUND
Lymphopenia is associated with various pathologies such as sepsis, burns, trauma, general anesthesia and major surgeries. All these pathologies are clinically expressed by the so-called Systemic Inflammatory Response Syndrome which does not include lymphopenia into defining criteria. The main objective of this work was to analyze the diagnosis of patients admitted to a hospital related to lymphopenia during hospital stay. In addition, we investigated the relationship of lymphopenia with the four levels of the Severity of Illness (SOI) and the Risk of Mortality (ROM).
METHOD AND FINDINGS
Lymphopenia was defined as Absolute Lymphocyte Count (ALC) <1.0 x109/L. ALC were analyzed every day since admission. The four levels (minor, moderate, major and extreme risk) of both SOI and ROM were assessed. A total of 58,260 hospital admissions were analyzed. More than 41% of the patients had lymphopenia during hospital stay. The mean time to death was shorter among patients with lymphopenia on admission 65.6 days (CI95%, 57.3-73.8) vs 89.9 (CI95%, 82.4-97.4), P<0.001. Also, patients with lymphopenia during hospital stay had a shorter time to the mortality, 67.5 (CI95%, 61.1-73.9) vs 96.9 (CI95%, 92.6-101.2), P<0.001.
CONCLUSIONS
Lymphopenia had a high prevalence in hospitalized patients with greater relevance in infectious pathologies. Lymphopenia was related and clearly predicts SOI and ROM at the time of admission, and should be considered as clinical diagnostic criteria to define SIRS.
Topics: Aged; Aged, 80 and over; Communicable Diseases; Female; Gastrointestinal Diseases; Hospital Mortality; Hospitals; Humans; Kidney Diseases; Length of Stay; Lung Diseases; Lymphocyte Count; Lymphopenia; Male; Middle Aged; Myeloproliferative Disorders; Retrospective Studies; Sepsis; Severity of Illness Index; Systemic Inflammatory Response Syndrome
PubMed: 34388210
DOI: 10.1371/journal.pone.0256205