Pulmonary vasculitis (Wegener's granulomatosis): Immunohistochemical study of T and B cell markers

doi:10.1016/0002-9343(83)91030-6

The American Journal of Medicine

Volume 74, Issue 4, April 1983, Pages 700-704

https://doi.org/10.1016/0002-9343(83)91030-6 Get rights and content

Abstract

A case of pulmonary vasculitis (Wegener's granulomatosis) is reported in which immunoperoxidase studies demonstrated that the vascular lymphoid infiltrates were composed predominantly of T cells and monocytes. Occasional T cells, B cells and monocytes were identified in the alveolar septa. IgG, IgA, IgM, and C3 were not identified in pulmonary vessels, septa, or alveoli. These findings suggest that cellular rather than humoral-immune mechanisms predominate in pulmonary vasculitis.

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The underlying mechanism of the reported vasculitis syndrome animal models is thought to be the deposition of immune complexes in blood vessels [1]. However, several human vasculitis syndromes such as granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis do not exhibit immune complex deposition [2]. Recently, the presence of disease-specific anti-neutrophil cytoplasmic antibody (ANCA) has been demonstrated for certain types of vasculitis, termed ANCA-associated vasculitis.
Here, we established CD4⁺αβTh1 clones specific for rat vascular smooth muscle antigen (VSMAg) that induced vasculitis lesions in the lungs of MRL/Mp-Fas^+/+ mice following adoptive transfer. Six different T cell clones, MV1b1 (Vβ1), MV1b4 (Vβ4), MV1b8.3 (Vβ8.3), MV1b61 (Vβ6), MV1b62 (Vβ6), and MV1b63 (Vβ6), were isolated from the MV1 T cell line from the regional lymph nodes of immunized MRL/Mp-Fas^+/+ mice; the three (Vβ6) clones had unique CDR3 amino acid sequences. Following stimulation with VSMAg-pulsed antigen presenting cells, MV1b61 and MV1b62 failed to secrete interferon-γ and tumor necrosis factor-α, although the other four clones secreted high levels of both cytokines. In adoptive transfer experiments, MV1b61 and MV1b62 did not induce organ involvement including pulmonary vasculitis. In contrast, MV1b1, MV1b4, MV1b8.3, and MV1b63 induced perivascular mononuclear cell infiltration in pulmonary small arteries. These clones may provide useful tools for investigating the underlying mechanisms of vasculitis syndromes and for developing therapeutic strategies.
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Citation Excerpt :
Finally, complement activation might also account for increased risk of venous thromboembolism observed in active AAV, as activated complement factors trigger coagulation.75,76 T cells are usually found within granulomas as well as in other lesions present in AAV.77–80 In accordance with these findings, elevated levels of markers of T-cell activity such as soluble interleukin-2 (IL-2) receptor, neopterin, and soluble CD30 as measured in the circulation have been shown to be associated with disease activity.81–83
ANCA-associated-vasculitis (AAV) comprises three different diseases entities: Churg–Strauss syndrome, microscopic polyangiitis, and Wegener’s granulomatosis. AAV is an autoimmune disease with complex pathophysiology. Anti-neutrophil cytoplasmic antibodies (ANCAs) with specificity for proteinase-3 (PR3) or myeloperoxidase (MPO) are hallmarks of AAV and have a pivotal role in disease development. In addition to ANCA, the cellular immune system contributes to the pathogenesis of the disease. ANCA-mediated degranulation of neutrophils causes vasculitic damage; T cells drive granuloma formation, promote vasculitic damage by several different pathways, and enhance autoantibody production by B cells. Recently, complementary PR3 and lysosomal membrane protein-2 were suggested as novel autoantigens in AAV. New findings also indicate the importance of complement, danger-associated molecular patterns, and dendritic cells in AAV. This review highlights novel pathophysiological findings in AAV and puts them into context with the current understanding of disease mechanisms. Furthermore, implications for present and new therapeutic strategies are discussed.
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2006, Kidney International
In order to test the hypothesis that Wegener's granulomatosis (WG) is associated with an ongoing immune effector response, even in remission, we examined the distribution of peripheral naive and memory T-lymphocytes in this disease, and analyzed the function-related phenotypes of the memory T-cell population. Peripheral blood mononuclear cells (PBMCs) were freshly isolated from WG-patients in remission (R-WG, n=40), active WG-patients (A-WG, n=17), and age-matched healthy controls (HCs, n=21). Expression of CD4, CD8, CD45RO, CCR7, interleukin (IL)-18Rα, ST2L, and FoxP3 were determined by four-color flow cytometric analysis. CD45RO and CCR7 were used for distinction between naive and memory T cells, IL-18Rα, ST2L, and FoxP3 for the assessment of Type1, Type2, and regulatory T-cells, respectively. In R-WG, the CD4⁺CD45RO⁺CCR7⁻ effector memory T-cell subpopulation (T_EM) was relatively increased, whereas the CD4⁺CD45RO⁻CCR7⁺ naive T-cell population (T_Naive) was decreased as compared to HC. The distribution of naive and memory CD8⁺T cells did not differ between R-WG, A-WG, and HC, nor did CD4⁺CD45RO⁺CCR7⁺ central memory T cells (T_CM). In contrast to HC, the percentage of CD4⁺T_Naive cells in R-WG correlated negatively with age, whereas CD4⁺T_EM cells showed a positive correlation. In R-WG, a skewing towards Type2 T cells was observed in CD4⁺T_EM cells. No differences were detected in FoxP3⁺CD4⁺T_EM cells between R-WG and A-WG, whereas the FoxP3⁻CD4⁺T_EM cells were increased in R-WG and decreased in A-WG as compared to HC. Collectively, peripheral blood homeostasis of CD4⁺T cells is disturbed in R-WG with the persistent expansion of non-regulatory CD4⁺T_EM cells. These cells might be involved in relapse and may constitute a target for therapy.
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¹: From the Department of Pathology and Pulmonary Medicine, Cleveland Clinic Foundation, Cleveland, Ohio.

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The American Journal of Medicine

Abstract

References (14)

Circulating immunoglobulin complexes in Wegener's granulomatosis

Am J Med

An ultrastructural study of the pathogenesis of tissue injury in limited Wegener's granulomatosis

Pathology

Wegener's granulomatosus. Electron microscopic and immunofluorescence studies

Chest

Wegener's granulomatosis: studies in 18 patients and a review of the literature

Medicine

Wegener's granulomatosis: pathology and review of the literature

Arch Pathol

Limited forms of angiitis and granulomatosis of Wegener's type

Am J Med

Treatment of Wegener's granulomatosis with immunosuppressive agents. Description of renal ultrastructures

Arch Intern Med

Cited by (63)

Isolation of vascular smooth muscle antigen-reactive CD4<sup>+</sup>αβTh1 clones that induce pulmonary vasculitis in MRL/Mp-Fas<sup>+/+</sup> mice

New pathophysiological insights and treatment of ANCA-associated vasculitis

Persistent expansion of CD4<sup>+</sup> effector memory T cells in Wegener's granulomatosis

Neuropathies with Systemic Vasculitis

Neuropathies with Systemic Vasculitis

Granulomatosis with Polyangiitis

Case reportPulmonary vasculitis (Wegener's granulomatosis): Immunohistochemical study of T and B cell markers

Abstract

Am J Med

Pathology

Chest

Wegener's granulomatosis: studies in 18 patients and a review of the literature

Medicine

Wegener's granulomatosis: pathology and review of the literature

Arch Pathol

Limited forms of angiitis and granulomatosis of Wegener's type

Am J Med

Treatment of Wegener's granulomatosis with immunosuppressive agents. Description of renal ultrastructures

Arch Intern Med

Case report
Pulmonary vasculitis (Wegener's granulomatosis): Immunohistochemical study of T and B cell markers