Granulomatous inflammation: The overlap of immune deficiency and inflammation

Rosé, Carlos D.; Neven, Bénédicte; Wouters, Carine

doi:10.1016/j.berh.2014.03.006

Cited by 30 publications

(13 citation statements)

References 88 publications

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“…Importantly, hypogammaglobulinemia may be one of the immunological abnormalities found in these primary immunodeficiencies. There are also several primary immunodeficiencies that have granulomatous inflammation in extrapulmonary locations [41]. As more patients with these rare diseases are diagnosed and additional monogenic cause of primary immunodeficiencies are described, we believe that the number of primary immunodeficiencies where GLILD is found will increase.…”

Section: Discussionmentioning

confidence: 99%

Granulomatous and lymphocytic interstitial lung disease: a spectrum of pulmonary histopathologic lesions in common variable immunodeficiency—histologic and immunohistochemical analyses of 16 cases

Rao¹,

Mackinnon²,

Routes³

2015

Human Pathology

111

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Common Variable Immunodeficiency (CVID) is a primary immunodeficiency of unknown etiology characterized by low serum IgG, a decreased ability to make specific antibodies, and variable T cell defects. Approximately 20% of patients with CVID develop clinical evidence of a diffuse parenchymal lung disease with a constellation of histopathological findings termed granulomatous and lymphocytic interstitial lung disease (GLILD). In this study, we characterized the histological and immunohistochemical features in a series of 16 cases diagnosed by open lung biopsy. Peribronchiolar and interstitial lymphocytic infiltration, granulomatous inflammation and organizing pneumonia were consistent features; interstitial fibrosis with architectural remodeling was also found in a subgroup of patients. By immunohistochemistry, a predominance of CD4+ T lymphocytes with variable numbers of CD8+ T cells and B cells were present, with a striking absence of FOXP3 positive T regulatory cells. This heretofore unrecognized immunohistochemical finding, needs further investigation for a potential role in the pathogenesis of the condition. The presence of interstitial fibrosis with or without architectural remodeling in a subset of patients also needs additional study, for effect on prognosis.

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Section: Discussionmentioning

confidence: 99%

Granulomatous and lymphocytic interstitial lung disease: a spectrum of pulmonary histopathologic lesions in common variable immunodeficiency—histologic and immunohistochemical analyses of 16 cases

Rao¹,

Mackinnon²,

Routes³

2015

Human Pathology

111

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“…Reports of hypomorphic RAG mutations preserving higher RAG activity level (averaging >30 %) are associated with the generation of near normal Tand B cell counts and risk for CID with immune dysregulation including granulomatous disease and/or autoimmunity [3]. Moreover, immune dysregulation marked by granulomatous disease and autoimmunity are seen across a wide spectrum of PIDD and may relate to abnormalities in T and B cell development as well as associated abnormalities in the cellular and/or cytokine environment [12]. The population frequency of pathogenic homozygous or compound heterozygous RAG1/2 variants is estimated to be about 1:6000 in individuals of European descent [5], thus we expect to find cases of partial RAG-deficiency more frequently in the era of next generation sequencing techniques such as gene panels and exome sequencing.…”

Section: Discussionmentioning

confidence: 99%

Identification of Patients with RAG Mutations Previously Diagnosed with Common Variable Immunodeficiency Disorders

et al. 2014

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Purpose Combined immunodeficiency (CID) presents a unique challenge to clinicians. Two patients presented with the prior clinical diagnosis of common variable immunodeficiency (CVID) disorder marked by an early age of presentation, opportunistic infections, and persistent lymphopenia. Due to the presence of atypical clinical features, next generation sequencing was applied documenting RAG deficiency in both patients. Methods Two different genetic analysis techniques were applied in these patients including whole exome sequencing in one patient and the use of a gene panel designed to target genes known to cause primary immunodeficiency disorders (PIDD) in a second patient. Sanger dideoxy sequencing was used to confirm RAG1 mutations in both patients. Results Two young adults with a history of recurrent bacterial sinopulmonary infections, viral infections, and autoimmune disease as well as progressive hypogammaglobulinemia, abnormal antibody responses, lymphopenia and a prior diagnosis of CVID disorder were evaluated. Compound heterozygous mutations in RAG1 (1) c256_257delAA, p86VfsX32 and (2) c1835A>G, pH612R were documented in one patient. Compound heterozygous mutations in RAG1 (1) c.1566G>T, p.W522C and (2) c.2689C>T, p. R897X) were documented in a second patient post-mortem following a fatal opportunistic infection. Conclusion Astute clinical judgment in the evaluation of patients with PIDD is necessary. Atypical clinical findings such as early onset, granulomatous disease, or opportunistic infections should support the consideration of atypical forms of late onset CID secondary to RAG deficiency. Next generation sequencing approaches provide powerful tools in the investigation of these patients and may expedite definitive treatments.

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“…Granulomatous tissue inflammation is a typical complication of immunodeficiency syndromes (7, 8), exemplifying the coexistence of defective immunity with autoimmune and granulomatous manifestations. In such immune-deficient patients, susceptibility to bacterial and fungal infections is combined with a high risk for excessive inflammation, promoting granuloma formation in essentially any organ system.…”

Section: Introductionmentioning

confidence: 99%

Pro-inflammatory and anti-inflammatory T cells in giant cell arteritis

et al. 2017

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Giant cell arteritis is an autoimmune disease defined by explicit tissue tropism to the walls of medium and large arteries. Pathognomic inflammatory lesions are granulomatous in nature, emphasizing the functional role of CD4 T cells and macrophages. Evidence for a pathogenic role of antibodies and immune complexes is missing. Analysis of T cell populations in giant cell arteritis, both in the tissue lesions and in the circulation, has supported a model of broad, polyclonal T cell activation, involving an array of functional T cell lineages. The signature of T cell cytokines produced by vasculitic lesions is typically multifunctional, including IL-2, IFN-γ, IL-17, IL-21, and GM-CSF, supportive for a general defect in T cell regulation. Recent data describing the lack of a lymph node-based population of anti-inflammatory T cells in giant cell arteritis patients offers a fresh look at the immunopathology of this vasculitis. Due to defective CD8+NOX2+ regulatory T cells, giant cell arteritis patients appear unable to curtail clonal expansion within the CD4 T cell compartment, resulting in wide-spread CD4 T cell hyperimmunity. Why unopposed expansion of committed CD4 effector T cells would lead to invasion of the walls of medium and large arteries needs to be explored in further investigations.

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Granulomatous inflammation: The overlap of immune deficiency and inflammation

Cited by 30 publications

References 88 publications

Granulomatous and lymphocytic interstitial lung disease: a spectrum of pulmonary histopathologic lesions in common variable immunodeficiency—histologic and immunohistochemical analyses of 16 cases

Granulomatous and lymphocytic interstitial lung disease: a spectrum of pulmonary histopathologic lesions in common variable immunodeficiency—histologic and immunohistochemical analyses of 16 cases

Identification of Patients with RAG Mutations Previously Diagnosed with Common Variable Immunodeficiency Disorders

Pro-inflammatory and anti-inflammatory T cells in giant cell arteritis

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