Overexpression of Bcl-2 Protein in Bronchoalveolar Lavage Lymphocytes and Macrophages in Sarcoidosis

Mermigkis, Charalampos; Polychronopoulos, Vlasis; Mermigkis, Dimitrios; Tsakanika, Konstantina; Heretis, M.; Karagianidis, Napoleon; Bouros, Demosthenes

doi:10.1159/000088688

Cited by 6 publications

(4 citation statements)

References 21 publications

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“…DAP, an ubiquitin homology protein, has been shown to suppress NF-kB/Rel activity, to interact with the death domain of TNF-R1 (Tumor necrosis factor receptor 1) and to trigger program cell death in a variety of cell lines (Liou and Liou 1999;Raveh et al 2000). The potential relevance is that a balance between apoptosis and inXammatory cell survival provides a fundamental mechanism for immune system homeostasis and one proposed mechanism for the chronic granulomatous inXammation in sarcoidosis is through altered apoptosis (Mermigkis et al 2005;Xaus et al 2003;Stridh et al 2002). Granzymes A and K (GZM A and K), located on chromosome 5q11-12 approximately 1.5 cM from D5S407, are serine proteases released from the granules of cytotoxic lymphocytes which induce apoptosis and are expressed in PBMCs (Bade et al 2005).…”

Section: Discussionmentioning

confidence: 99%

Genetic characterization and fine mapping of susceptibility loci for sarcoidosis in African Americans on chromosome 5

et al. 2006

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Sarcoidosis, a systemic granulomatous disease, likely results from both environmental agents and genetic susceptibility. Sarcoidosis is more prevalent in women and, in the United States, African Americans are both more commonly and more severely affected than Caucasians. We report a follow up of the first genome scan for sarcoidosis susceptibility genes in African Americans. Both the genome scan and the present study comprise 229 African American nuclear families ascertained through two or more sibs with sarcoidosis. Regions studied included those which reached a significance in the genome scan of 0.01 (2p25, 5q11, 5q35, 9q34, 11p15 and 20q13), 0.05 (3p25 and 5p15-13) or which replicated previous findings (3p14-11). We performed genotyping with additional markers in the same families used in the genome scan. We examined multi-locus models for epistasis and performed model-based linkage analysis on subsets of the most linked families to characterize the underlying genetic model. The strongest signal was at marker D5S407 (P=0.005) on 5q11.2, using both full and half sibling pairs. Our results support, in an African American population, a sarcoidosis susceptibility gene on chromosome 5q11.2, and a gene protective for sarcoidosis on 5p15.2. These fine mapping results further prioritize the importance of candidate regions on chromosomes 2p25, 3p25, 5q35, 9q34, 11p15 and 20q13 for African Americans. Additionally, our results suggest joint action of the effects of putative genes on chromosome 3p14-11 and 5p15.2. We conclude that multiple susceptibility loci for sarcoidosis exist in African Americans and that some may have interdependent effects on disease pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Genetic characterization and fine mapping of susceptibility loci for sarcoidosis in African Americans on chromosome 5

et al. 2006

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“…However, a current paradigm posits that peripheral depletion of lymphocytes results from an imbalance between immunoregulatory and effector T-cell numbers and function in response to prolonged antigenic exposure ( 6 , 8 , 12 – 14 ). This notion is supported by conventional studies that demonstrate aberrant expression of CD28, CD95 (Fas), CD274 (PD-1), and other molecules linked to programmed cell death and points towards inherent molecular mechanisms contributing to T-cell anergy or exhaustion and development of lymphopenia in sarcoidosis ( 4 , 6 – 8 , 11 , 14 – 17 ). Accordingly, lymphopenia and loss of effector function is thought to impair immune surveillance and inhibit downregulation of immune reactions thereby eliciting a state of persistent maladaptive inflammatory activity that, in turn, prevents disease resolution and promotes development of chronic disease ( 4 , 7 , 13 , 14 , 18 – 26 ).…”

Section: Introductionmentioning

confidence: 77%

Altered transcription factor targeting is associated with differential peripheral blood mononuclear cell proportions in sarcoidosis

et al. 2022

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IntroductionIn sarcoidosis, peripheral lymphopenia and anergy have been associated with increased inflammation and maladaptive immune activity, likely promoting development of chronic and progressive disease. However, the molecular mechanisms that lead to reduced lymphocyte proportions, particularly CD4+ T-cells, have not been fully elucidated. We posit that paradoxical peripheral lymphopenia is characterized by a dysregulated transcriptomic network associated with cell function and fate that results from altered transcription factor targeting activity.MethodsMessenger RNA-sequencing (mRNA-seq) was performed on peripheral blood mononuclear cells (PBMCs) from ACCESS study subjects with sarcoidosis and matched controls and findings validated on a sarcoidosis case-control cohort and a sarcoidosis case series. Preserved PBMC transcriptomic networks between case-control cohorts were assessed to establish cellular associations with gene modules and define regulatory targeting involved in sarcoidosis immune dysregulation utilizing weighted gene co-expression network analysis and differential transcription factor involvement analysis. Network centrality measures identified master transcriptional regulators of subnetworks related to cell proliferation and death. Predictive models of differential PBMC proportions constructed from ACCESS target gene expression corroborated the relationship between aberrant transcription factor regulatory activity and imputed and clinical PBMC populations in the validation cohorts.ResultsWe identified two unique and preserved gene modules significantly associated with sarcoidosis immune dysregulation. Strikingly, increased expression of a monocyte-driven, and not a lymphocyte-driven, gene module related to innate immunity and cell death was the best predictor of peripheral CD4+ T-cell proportions. Within the gene network of this monocyte-driven module, TLE3 and CBX8 were determined to be master regulators of the cell death subnetwork. A core gene signature of differentially over-expressed target genes of TLE3 and CBX8 involved in cellular communication and immune response regulation accurately predicted imputed and clinical monocyte expansion and CD4+ T-cell depletion.ConclusionsAltered transcriptional regulation associated with aberrant gene expression of a monocyte-driven transcriptional network likely influences lymphocyte function and survival. Although further investigation is warranted, this indicates that crosstalk between hyperactive monocytes and lymphocytes may instigate peripheral lymphopenia and underlie sarcoidosis immune dysregulation and pathogenesis. Future therapies selectively targeting master regulators, or their targets, may mitigate dysregulated immune processes in sarcoidosis and disease progression.

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“…Po drugie, choroby z grupy ILD przebiegające z limfocytozą BAL (jak sarkoidoza, EAA i beryloza) charakteryzują się z reguły mniejszą częstością apoptozy AL lub zwiększoną opornością komórek na ten proces, w porównaniu z grupą kontrolną [82][83][84]. Natomiast w idiopatycznym włóknieniu płuc (IPF, idiopathic pulmonary fibrosis) częstość apoptozy AL jest znamiennie większa [32].…”

Section: Limfocyty Pęcherzykowe Jako Przedmiot Miejscowej Apoptozyunclassified

“…Tymczasem, zastrzegając, że w każdej z ILD mechanizm zaprogramowanej śmierci limfocytów dolnych dróg oddechowych może być odmienny, autorzy przychylają się do stanowiska, że zasadniczą przyczyną apoptozy AL w ILD jest NID, zaś AICD pełni rolę modulującą. Kluczowe znaczenie regulacyjne w apoptozie limfocytów miałaby nierównowaga między parą ich najważniejszych czynników szlaku mitochondrialnego, antyapoptotycznym białkiem BCL-2, a jego antagonistą, należącym do podrodziny BH3-only, białkiem BIM (główna rola kontrolna przypada prawie na pewno IL-2) [1,84].…”

Section: Limfocyty Pęcherzykowe Jako Przedmiot Miejscowej Apoptozyunclassified

Apoptoza limfocytów pęcherzykowych. Część 1—Szlaki apoptozy limfocytów

Kopiński¹,

Chorostowska‐Wynimko²,

Dyczek³

et al. 2014

Advances in Respiratory Medicine

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Apoptosis is a form of programmed cell death essential for maintaining homeostasis, including onset, progress and resolution of immune reactions. Two major apoptosis pathways: extrinsic (mediated by death receptors) and intrinsic (mitochondrial), were distinguished. Lymphocytes with cytotoxic activity may also initiate apoptosis of target cells by granzyme/perforin (pseudoreceptor) pathway. The specific apoptotic processes, i.e. activation induced cell death (AICD) and neglect induced death (NID), are types of extrinsic and intrinsic pathways, respectively. They both seem to be crucial in apoptosis of antigen-primed T cells during the contraction phase of inflammation. Alveolar lymphocytes (AL) are almost exclusively T effector cells, engaged in interstitial lung disease (ILD) pathophysiologies. The AL numbers in lower airways depends on recruitment to the lung, proliferation and local apoptosis. According to the references, it should be noted that AL usually do not proliferate in alveoli; their apoptosis rate accounts, on average, for 1% of cells in healthy subjects, and this is significantly decreased in disorders with lymphocytic alveolitis such as sarcoidosis and extrinsic allergic alveolitis (EAA). The mechanisms of AL apoptosis have not been completely explained. However, it is the NID process that is probably critical for the culling of T-cell response, as in EAA or sarcoidosis remission, with AICD as an auxiliary and/or modulating mechanism only. It should be emphasised that many ILDs are chronic disorders with no remission or improvement, and it is difficult to describe the AL response in terms of immune expansion/contraction.

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Overexpression of Bcl-2 Protein in Bronchoalveolar Lavage Lymphocytes and Macrophages in Sarcoidosis

Cited by 6 publications

References 21 publications

Genetic characterization and fine mapping of susceptibility loci for sarcoidosis in African Americans on chromosome 5

Genetic characterization and fine mapping of susceptibility loci for sarcoidosis in African Americans on chromosome 5

Altered transcription factor targeting is associated with differential peripheral blood mononuclear cell proportions in sarcoidosis

Apoptoza limfocytów pęcherzykowych. Część 1—Szlaki apoptozy limfocytów

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