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Immunologic Factors.

There are several immunologic abnormalities in the local milieu of sarcoid granulomas that suggest the development of a cell-mediated response to an unidentified antigen. The process is

driven by CD4+ helper T cells. These abnormalities include:[72]

• Intra-alveolar and interstitial accumulation of CD4+ T cells, resulting in CD4:CD8 T-cell ratios ranging from 5:1 to 15:1. There is oligoclonal expansion of T-cell subsets as

determined by analysis of T-cell receptor rearrangement, suggesting an antigen-driven proliferation.

• Increased levels of T cell-derived TH 1 cytokines such as IL-2 and interferon-g (IFN-g), resulting in T-cell expansion and macrophage activation, respectively.

• Increased levels of several cytokines in the local environment (IL-8, TNF, macrophage inflammatory protein 1a [MIP-1a]) that favor recruitment of additional T cells and

monocytes and contribute to the formation of granulomas. TNF in particular is released at high levels by activated alveolar macrophages, and the TNF level in the bronchoalveolar

fluid is a marker of disease activity.

Additionally, there are systemic immunologic abnormalities in patients with sarcoidosis:

• Anergy to common skin test antigens such as Candida or purified protein derivative (PPD)

• Polyclonal hypergammaglobulinemia, another manifestation of helper T-cell dysregulation

Genetic Factors.

Evidence of genetic influences can be seen:

• Familial and racial clustering of cases

• Association with certain HLA genotypes (e.g., class I HLA-A1 and HLA-B8)

Environmental Factors.

These are possibly the most tenuous of all the associations in the pathogenesis of sarcoidosis. Several putative microbes have been proposed as the inciting agent for sarcoidosis (e.g.,

mycobacteria, Propionibacterium acnes, and Rickettsia species).[73] To date, there is no unequivocal evidence to suggest that sarcoidosis is caused by an infectious agent.

Morphology.

Histologically, all involved tissues show the classic noncaseating granulomas( Fig. 15-23 ), each composed of an aggregate of tightly clustered epithelioid cells, often with Langhans or

foreign body type giant cells. Central necrosis is unusual. With chronicity, the granulomas may become enclosed within fibrous rims or may eventually be replaced by hyaline fibrous

scars. Two other microscopic features are often present in the granulomas: (1) laminated concretions composed of calcium and proteins known as Schaumann bodies and (2) stellate

inclusions known as asteroid bodies enclosed within giant cells found in approximately 60% of the granulomas. Although characteristic, these microscopic features are not pathognomonic

of sarcoidosis because asteroid and Schaumann bodies may be encountered in other granulomatous diseases (e.g., tuberculosis). Pathologic involvement of virtually every organ in the body

has been cited at one time or another.

The lungsare common sites of involvement. [74] Macroscopically, there is usually no demonstrable alteration, although at times, the coalescence of granulomas may produce small nodules



that are palpable or visible as 1- to 2-cm, noncaseating, noncavitated consolidations. Histologically, the lesions are distributed primarily along the lymphatics, around bronchi and blood

vessels, although alveolar lesions are also seen. The relative frequency of granulomas in the bronchial submucosa accounts for the high diagnostic yield of bronchoscopic biopsies. A CD4/

CD8 ratio >2.5 and the CD3/CD4 ratio <0.31 in bronchoalveolar lavage lymphocytes is commonly seen in sarcodosis.[75] There appears to be a strong tendency for

Figure 15-23Characteristic sarcoid noncaseating granulomas in lung with many giant cells. (Courtesy of Dr. Ramon Blanco, Department of Pathology, Brigham and Women's Hospital,

Boston, MA.)

Figure 15-24Hypersensitivity pneumonitis, histologic appearance. Loosely formed interstitial granulomas and chronic inflammation are characteristic.

Figure 15-25Desquamative interstitial pneumonia: medium-power detail of lung to demonstrate the accumulation of large numbers of mononuclear cells within the alveolar spaces with

only mild fibrous thickening of the alveolar walls.

Figure 15-26Pulmonary alveolar proteinosis, histologic appearance. The alveoli are filled with a dense, amorphous, protein-lipid granular precipitate, while the alveolar walls are normal.

Figure 15-27Large saddle embolus from the femoral vein lying astride the main left and right pulmonary arteries. (From the teaching collection of the Department of Pathology,

University of Texas Southwestern Medical School, Dallas, TX.)

Figure 15-28Recent, small, roughly wedge-shaped hemorrhagic pulmonary infarct.

Figure 15-29Pathogenesis of primary pulmonary hypertension.

Figure 15-30Vascular changes in pulmonary hypertension. A, Gross photograph of atheroma formation, a finding usually limited to large vessels. B, Marked medial hypertrophy. C,

Plexogenic lesion characteristic of advanced pulmonary hypertension seen in small arteries.

Figure 15-31Acute intra-alveolar hemorrhage and hemosiderin-laden macrophages, reflecting previous hemorrhage, are common features of the diffuse pulmonary hemorrhage syndromes

(Prussian blue stain for iron).

TABLE 15-8-- The Pneumonia Syndromes


Date: 2016-04-22; view: 728


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