Why is lymphoid organization important? The evolution of specialized antigen-presenting cells, B cells and T cells, all of which need to interact for successful immune responses, requires mechanisms for these cells to find each other and additional mechanisms to support their proliferation and survival during immune responses ^[14]. In this regard, the development of specialized stromal cells, including fibroblastic reticular cells (FRCs) in the T cell area and follicular dendritic cells (FDCs) in the B cell area, is likely a key innovation. These cell types provide the scaffolding of lymphoid organs and help to spatially organize lymphocytes and antigen-presenting cells. For example, FRCs express the chemokine CCL19, which attracts T cells and activated dendritic cells (DCs) into the T cell zone ^{[18], [19]}, whereas FDCs express the chemokines CXCL12 and CXCL13, which attract B cells and T follicular helper (Tfh) cells and direct their spatial positioning in the B cell follicle and germinal center ^{[20], [21], [22], [23]}. Although B and T cell separation occurs in amphibians and reptiles, identifiable stromal cells such as FDCs are observed only in birds and mammals ^[14] (Fig. 2.1), which probably explains why these species (and not others) are able to support germinal center responses and generate high-affinity antibodies ^{[24], [25]}. Thus the mechanisms that control the differentiation of stromal cell elements are critical for the proper organization and function of lymphoid organs.

The common and distinct mechanisms of protective and pathogenic iBALT formation. 1) Protective iBALT is induced in response to PAMPs recognized by PRR expressed on innate immune cells or epithelial cells. Pathogenic iBALT is induced in response to chronic pathogen exposure, self-antigens, or environmental Ags, which induce DAMPs and inflammation. 2) The sensing of PAMPs and DAMPs results in the production of iBALT-driving cytokines that induce the local response of myeloid cells, production of inflammatory molecules, and recruitment of more myeloid cells, lymphocytes, FDCs, and Tfh. 3) These signals and associated cellular recruitment drive the formation and organization of GC. 4) In protective iBALT, responses are associated with early recruitment of neutrophils and cDCs, IFN-γ–mediated pathogen clearance, and short-term inflammation. In pathogenic iBALT, responses are associated with autoantibodies and uncontrolled inflammation, with some diseases specifically highlighted by eosinophilia-induced inflammation. Other changes include altered metabolic state and dysregulated lymphocyte proliferation with subsequent long-term unresolved inflammation.