Severe persistent mycobacteria antigen stimulation causes lymphopenia through impairing hematopoiesis

Li, Fēi; Yin, Ma; Li, Xiaoping; Zhang, Dan; Han, Jiangyuan; Tan, D. S. K.; Mi, Youjun; Xiao, Yang; Wang, Juan; Zhu, Bin

doi:10.3389/fcimb.2023.1079774

Cited by 7 publications

(14 citation statements)

References 46 publications

(60 reference statements)

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“…Tuberculosis-associated aplastic cytopenia has even been reported in Bacillus Calmette-Guerin vaccination[ 23 ]. Tuberculosis infection can trigger cellular immune responses and lead to the excessive production of proinflammatory cytokines[ 24 , 25 ], thereby inducing immune-mediated hematopoietic injury[ 26 , 27 ]. Gut involvement of tuberculosis infection likely plays a more important role because tuberculosis-induced aplastic cytopenia has been reported merely in disseminated tuberculosis instead of isolated pulmonary tuberculosis.…”

Section: Discussionmentioning

confidence: 99%

Tuberculosis-induced aplastic crisis and atypical lymphocyte expansion in advanced myelodysplastic syndrome: A case report and review of literature

Sun¹,

Yang²,

Xu³

et al. 2023

World J Clin Cases

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BACKGROUND Myelodysplastic syndrome (MDS) is caused by malignant proliferation and ineffective hematopoiesis. Oncogenic somatic mutations and increased apoptosis, necroptosis and pyroptosis lead to the accumulation of earlier hematopoietic progenitors and impaired productivity of mature blood cells. An increased percentage of myeloblasts and the presence of unfavorable somatic mutations are signs of leukemic hematopoiesis and indicators of entrance into an advanced stage. Bone marrow cellularity and myeloblasts usually increase with disease progression. However, aplastic crisis occasionally occurs in advanced MDS. CASE SUMMARY A 72-year-old male patient was definitively diagnosed with MDS with excess blasts-1 (MDS-EB-1) based on an increase in the percentages of myeloblasts and cluster of differentiation (CD)34+ hematopoietic progenitors and the identification of myeloid neoplasm-associated somatic mutations in bone marrow samples. The patient was treated with hypomethylation therapy and was able to maintain a steady disease state for 2 years. In the treatment process, the advanced MDS patient experienced an episode of progressive pancytopenia and bone marrow aplasia. During the aplastic crisis, the bone marrow was infiltrated with sparsely distributed atypical lymphocytes. Surprisingly, the leukemic cells disappeared. Immunological analysis revealed that the atypical lymphocytes expressed a high frequency of CD3, CD5, CD8, CD16, CD56 and CD57, suggesting the activation of autoimmune cytotoxic T-lymphocytes and natural killer (NK)/NKT cells that suppressed both normal and leukemic hematopoiesis. Elevated serum levels of inflammatory cytokines, including interleukin (IL)-6, interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), confirmed the deranged type I immune responses. This morphological and immunological signature led to the diagnosis of severe aplastic anemia secondary to large granule lymphocyte leukemia. Disseminated tuberculosis was suspected upon radiological examinations in the search for an inflammatory niche. Antituberculosis treatment led to reversion of the aplastic crisis, disappearance of the atypical lymphocytes, increased marrow cellularity and 2 mo of hematological remission, providing strong evidence that disseminated tuberculosis was responsible for the development of the aplastic crisis, the regression of leukemic cells and the activation of CD56+ atypical lymphocytes. Reinstitution of hypomethylation therapy in the following 19 mo allowed the patient to maintain a steady disease state. However, the patient transformed the disease phenotype into acute myeloid leukemia and eventually died of disease progression and an overwhelming infectious episode. CONCLUSION Disseminated tuberculosis can induce CD56+ lymphocyte infiltration in the bone marrow and in turn suppress both normal and leukemic hematopoiesis, resulting in the development of aplastic crisis and leukemic cell regression.

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Section: Discussionmentioning

confidence: 99%

Tuberculosis-induced aplastic crisis and atypical lymphocyte expansion in advanced myelodysplastic syndrome: A case report and review of literature

Sun¹,

Yang²,

Xu³

et al. 2023

World J Clin Cases

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“…However, chronic inflammatory stress in response to persistent intracellular infections can induce Th1-predominant immune responses and exhaust host hematopoietic functions. These responses predominantly exhaust granulopoiesis, erythropoiesis, megakaryocytopoiesis, and B lymphopoiesis ( 311 – 316 ) and result in the morphological and immunological signatures shown in AHF ( 3 , 4 , 10 , 240 ). The upregulated expression of HLA-DR, TLRs, and the Nlrp3 inflammasome due to the primary immune-active BME increases sensitivity to antigen stimulation ( 50 , 52 , 66 , 67 ) and apoptotic death of HPCs ( 50 , 62 , 63 ).…”

Section: Reversion Of the Immune-exhausted State By Th1 Responses And...mentioning

confidence: 99%

“…Gastrointestinal and even isolated pulmonary tuberculosis can induce pathological processes in the gastrointestinal tract, not only alone but also in combination with gut dysbiosis, which results in diffuse gut inflammatory lesions ( 181 , 381 , 382 ). In this setting, both pathogenic and commensal ( 185 , 186 ) microbes, in addition to M. tuberculosis infection ( 315 , 316 ), become exogenous antigens to sustain deranged immune responses.…”

Section: Particular Attention Should Be Given To Gut Inflammatory Dis...mentioning

confidence: 99%

When inflammatory stressors dramatically change, disease phenotypes may transform between autoimmune hematopoietic failure and myeloid neoplasms

Zhao,

Ju,

Xiu

et al. 2024

Front. Immunol.

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Aplastic anemia (AA) and hypoplastic myelodysplastic syndrome are paradigms of autoimmune hematopoietic failure (AHF). Myelodysplastic syndrome and acute myeloid leukemia are unequivocal myeloid neoplasms (MNs). Currently, AA is also known to be a clonal hematological disease. Genetic aberrations typically observed in MNs are detected in approximately one-third of AA patients. In AA patients harboring MN-related genetic aberrations, a poor response to immunosuppressive therapy (IST) and an increased risk of transformation to MNs occurring either naturally or after IST are predicted. Approximately 10%–15% of patients with severe AA transform the disease phenotype to MNs following IST, and in some patients, leukemic transformation emerges during or shortly after IST. Phenotypic transformations between AHF and MNs can occur reciprocally. A fraction of advanced MN patients experience an aplastic crisis during which leukemic blasts are repressed. The switch that shapes the disease phenotype is a change in the strength of extramedullary inflammation. Both AHF and MNs have an immune-active bone marrow (BM) environment (BME). In AHF patients, an inflamed BME can be evoked by infiltrated immune cells targeting neoplastic molecules, which contributes to the BM-specific autoimmune impairment. Autoimmune responses in AHF may represent an antileukemic mechanism, and inflammatory stressors strengthen antileukemic immunity, at least in a significant proportion of patients who have MN-related genetic aberrations. During active inflammatory episodes, normal and leukemic hematopoieses are suppressed, which leads to the occurrence of aplastic cytopenia and leukemic cell regression. The successful treatment of underlying infections mitigates inflammatory stress-related antileukemic activities and promotes the penetration of leukemic hematopoiesis. The effect of IST is similar to that of treating underlying infections. Investigating inflammatory stress-powered antileukemic immunity is highly important in theoretical studies and clinical practice, especially given the wide application of immune-activating agents and immune checkpoint inhibitors in the treatment of hematological neoplasms.

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“…Additionally, both CD4 + and CD8 + T cell counts are decreased in active TB patients [15,18]. Lymphopenia is defined as lymphocyte percentage (the percentage of lymphocyte count to leukocyte count) < 20% or absolute lymphocyte count < 10 9 cells/L [10,19]. Specifically, lymphopenia was found in 46% of untreated pulmonary TB patients [20] and 76.92% of patients with miliary TB [10], revealing that lymphopenia may be a prominent feature of severe TB infection [21].…”

Section: Lymphopenia Is Common In Tb Patientsmentioning

confidence: 99%

“…Some severe TB patients even need to be admitted to the intensive care unit (ICU) [9]. Severe TB can cause various complications, including severe weight loss, anemia, and lymphopenia, ultimately leading to death [10][11][12]. The mortality rates for these severe forms range from 15.5% to 65.9% [13,14].…”

Section: Introductionmentioning

confidence: 99%

Possible Mechanisms of Lymphopenia in Severe Tuberculosis

Li,

Chen,

Zeng

et al. 2023

Microorganisms

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Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (M. tuberculosis). In lymphopenia, T cells are typically characterized by progressive loss and a decrease in their count results. Lymphopenia can hinder immune responses and lead to systemic immunosuppression, which is strongly associated with mortality. Lymphopenia is a significant immunological abnormality in the majority of patients with severe and advanced TB, and its severity is linked to disease outcomes. However, the underlying mechanism remains unclear. Currently, the research on the pathogenesis of lymphopenia during M. tuberculosis infection mainly focuses on how it affects lymphocyte production, survival, or tissue redistribution. This includes impairing hematopoiesis, inhibiting T-cell proliferation, and inducing lymphocyte apoptosis. In this study, we have compiled the latest research on the possible mechanisms that may cause lymphopenia during M. tuberculosis infection. Lymphopenia may have serious consequences in severe TB patients. Additionally, we discuss in detail potential intervention strategies to prevent lymphopenia, which could help understand TB immunopathogenesis and achieve the goal of preventing and treating severe TB.

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Severe persistent mycobacteria antigen stimulation causes lymphopenia through impairing hematopoiesis

Cited by 7 publications

References 46 publications

Tuberculosis-induced aplastic crisis and atypical lymphocyte expansion in advanced myelodysplastic syndrome: A case report and review of literature

Tuberculosis-induced aplastic crisis and atypical lymphocyte expansion in advanced myelodysplastic syndrome: A case report and review of literature

When inflammatory stressors dramatically change, disease phenotypes may transform between autoimmune hematopoietic failure and myeloid neoplasms

Possible Mechanisms of Lymphopenia in Severe Tuberculosis

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