What are the immunopathologic features of sarcoidosis?
The defining pathologic feature of sarcoidosis is noncaseating granulomas, and any tissue may become involved. The major hypothesis of the ACCESS (A Case Control Etiologic Study of Sarcoidosis,) investigators was that sarcoidosis occurs in genetically susceptible individuals through alteration in immune response after exposure to an environmental, occupational, or infectious agent. Because the lungs are involved in 95% of those affected, it is likely that initial exposure to an inciting environmental or infectious agent is via the pulmonary route. Although the specific antigen(s) responsible for sarcoidosis is/are unknown, it is generally accepted that this disease occurs in response to antigen-driven activation of macrophages and T-lymphocytes.
Genetic factors play a role in the racial and ethnic variations in prevalence, clinical presentations, and severity of sarcoidosis. Human leukocyte antigen class II molecules on antigen-presenting cells (type II alveolar epithelial cells, macrophages, dendritic cells) present the antigen to CD4+ T-helper (T H 1) lymphocytes. This results in an amplified immune response with increased secretion of T H 1 cytokines including interferon-gamma (IFN-γ), interleukin (IL)-2, and TNF, increased tissue permeability, and cell migration. Additionally, there is dysfunctional regulatory T-cell (Treg) responses and expansion of IL-17 and IFN-γ producing T H 17 cells. Ultimately, there is clonal expansion of CD4+ T lymphocytes in response to the antigen(s) resulting in persistent inflammation, noncaseating granuloma formation, and potential fibrosis of involved organs.
In early and active disease, the bronchoalveolar lavage (BAL) fluid reveals an elevated lymphocyte count and a marked increase in CD4/CD8 T-lymphocyte ratio (>3.5). Additionally, there is an influx of T-helper cells and elevated ratio of CD4/CD8 T-cell subsets in other affected organs, hyperactivity of B cells, and circulation of immune complexes. Typical clinical observations related to these immunologic events include peripheral lymphopenia (due to sequestration at the site of inflammation), a low CD4/CD8 T-cell ratio in peripheral blood, cutaneous anergy, polyclonal gammopathy (30%–80%), and autoantibody production (low titer rheumatoid factor and/or antinuclear antibody in approximately one-third of patients).
