GranulomaL92.2

Virchow R. 1863

Nodular or nodular accumulation of cells that forms in the course of chronic inflammation and consists mainly of macrophages or their derivatives (epithelioid cells = stimulated, densely clustered macrophages; multinucleated giant cells = fused macrophages). Granulomatous inflammations used to be called specific inflammations. Today, it is assumed that only orienting conclusions about the underlying disease are possible from the granuloma structure.

• tuberculoid granuloma
• pseudotuberculoid granuloma
• Sarcoid granuloma (see below sarcoidosis)
• Foreign body granuloma
• Rheumatic granuloma (see below rheumatic nodules)
• Rheumatic nodules (for rheumatism nodosum)
• Lipophageal granuloma.

Granulomas are to be understood as chronic inflammations with different etiologies. They occur in infectious diseases (tuberculosis, leishmaniasis, syphilis), as free body reactions (silica, asbestos, silicones, plant components) or idiopathically, as a hypersensitivity reaction in diseases such as granuloma anulare or sarcoidosis.

The "containment" of a pathogen is suspected to be the target of a granulomatous tissue reaction. Thus, in the case of a microbial agent, the granuloma is described as a "stable unit" of the infection, which prevents the infection from spreading systemically. The cytokines associated with a Th1 response play a decisive role in the development of granulomas, especially interleukin-12 and interferon gamma. Interleukin-12 or interferon gamma deficient mice can only develop granulomas with a delay or not at all.

On the other hand, granuloma formation can also be seen as an advantage for the pathogen, since the immune system is apparently not able to eliminate the pathogen completely.

In granulomatous foreign body reactions, the size, composition and structural nature of the foreign body play a major role. Typical examples are granulomatous tissue reactions to asbestos needles, to endogenous keratin components or plant spines.

Not every foreign material that penetrates the skin causes a granulomatous tissue reaction. An example of this is the coal particles in the skin of a miner, or the finest color particles in tattoos which can remain freely in the tissue or stored in macrophages at the invasion site without reaction. Here an immunological tolerance has occurred. Even free dermal melanin (in pigment incontinence) or amyloid in cutaneous amyloidosis do not induce a granulomatous local reaction. However, other endogenous substances such as keratin components from a leaking epithelial cyst always cause granulomatous tissue reactions.

The classical architecture of the "mature" granuloma consists of a concentric lymphocyte infiltrate, which in its interior contains mainly CD68+, antigen-presenting cells, epitheloid cells, multinucleated giant cells, as well as CD4+ and CD45RO+ memory cells. CD8+ T cells dominate in the outer layer. This is followed by B cells in active follicle-like centers that resemble secondary lymphoid organs.

As a special feature, the granuloma formation that lasts for weeks in infections with Mycobacterium tuberculosis, is the central "cheesing". This only occurs with a minimum granuloma volume of 0.1 cbmm (Ulrichs T et al. 2004) and its immunological relevance is unclear. Probably, however, the necrobiotic material consists of attenuated foam macrophages (from Stebut E 2017).

The process of granuloma formation is phased.

Early granuloma: Specific immune signals lead to a focal recruitment and accumulation of mononuclear myeloid cells(macrophages) in the tissue. Unknown immunological signals lead to the formation of multinucleated giant cells.

Mature granuloma: In this phase the typical structure of the granuloma is visible with a histiocytic nucleus and a surrounding lymphocyte mantle. This consists primarily of T lymphocytes, but also of associated B cells, neutrophil and eosinophilic granulocytes, plasma cells (e.g. very prominent in the syphilitic tissue reaction). This predominantly Th1-associated inflammatory process serves to maintain a stable granuloma structure. The Th1 immune response with the interferon-gamma producing Th1 cells is the basis for fighting intracellular pathogens such as mycobacteria or leishmania. Interferon-gamma leads to an activation of M1-macrophages which enables them to kill the pathogens.

The chronic granuloma: After successful elimination of the triggering agent, anti-inflammatory signals lead to a regression of the granulomatous reaction. If this signal is missing, this leads to a long-term, considerable fibrotic remodelling of the parenchyma with various disturbances of tissue function (e.g. in sarcoidosis and anular granuloma).

1. Ulrichs T et al (2004) Human tuberculous granulomas induce peripheral lymphoid follicle-like structures to orchestrate local host defence in the lung. J Pathol 204:217-228.
2. by Stebut E (2017) What is a granuloma? Dermatologist 68: 520-525.