Immune mechanisms of granuloma formation in sarcoidosis and tuberculosis

Abstract

Sarcoidosis is a complex immune-mediated disease characterized by clusters of immune cells called granulomas. Despite major steps in understanding the cause of this disease, many questions remain. In this Review, we perform a mechanistic interrogation of the immune activities that contribute to granuloma formation in sarcoidosis and compare these processes with its closest mimic, tuberculosis, highlighting shared and divergent immune activities. We examine how Mycobacterium tuberculosis is sensed by the immune system; how the granuloma is initiated, formed, and perpetuated in tuberculosis compared with sarcoidosis; and the role of major innate and adaptive immune cells in shaping these processes. Finally, we draw these findings together around several recent high-resolution studies of the granuloma in situ that utilized the latest advances in single-cell technology combined with spatial methods to analyze plausible disease mechanisms. We conclude with an overall view of granuloma formation in sarcoidosis.

Figure 1. Schema of key immune features and immune cells (other than macrophages, MCGs, and epithelioid cells) involved or found in TB granuloma and sarcoidosis granuloma.

Each panel proposes a timeline of involvement and relative abundance for each of the immune cells and major processes within (A) TB granuloma and (B) sarcoidosis granuloma. Each granuloma is thought to act as its own immune entity with its own trajectory.

Figure 2. Diagram of TB granuloma and sarcoidosis granuloma.

Each panel includes proposed key immune cells, key cytokines (the size of the font corresponds to prominence), and structural differences in (A) TB granuloma and (B) sarcoidosis granuloma. Note that granuloma is a dynamic structure. See Figure 1 for the corresponding changes during granuloma evolution, from initiation to resolution or chronicity. Mtb, M. tuberculosis.