Novel insights: crosstalk with non-puerperal mastitis and immunity

Abstract

The two primary types of non-puerperal mastitis (NPM) are granulomatous lobular mastitis (GLM) and plasma cell mastitis (PCM). Existing research indicates that immune inflammatory response is considered to be the core of the pathogenesis of GLM and PCM, and both innate and adaptive immune responses play an important role in the pathophysiology of PCM and GLM. However, the regulatory balance between various immune cells in these diseases is still unclear. Consequently, we present a comprehensive summary of the immune-related variables and recent advances in GLM and PCM.

Keywords: granulomatous lobular mastitis; immune cell; immunity; non-puerperal mastitis; plasma cell mastitis; prolactin; review.

Figure 1

In the upper part of Figure 1 , the local microenvironment of a normal mammary duct is shown schematically. The epithelial cells of the normal ducts are tightly packed, the epithelial basement membrane is continuous, and a very small number of immune cells are present locally in the tissue. In the lower part of Figure 1 , the local microenvironment of the ducts of PCM is illustrated. Milk stasis exists in the ducts of PCM, and lipids and antibodies in the milk can activate the local immune response, resulting in damage to the epithelial cells of the ducts, enlarged cell gaps, and incomplete epithelial basement membranes, with a large number of plasma-cell-based inflammatory cells infiltrating the tissues. IL-6 plays an important role in PCM by promoting the differentiation of B cells into plasma cells and the release of antibodies. In addition, when IL-6 binds to IL-6R on the cell surface, Janus kinase (JAK) is phosphorylated, and then STAT3 is phosphorylated, which promotes downstream Bcl-2 expression and inhibits plasma cell apoptosis. On the other hand, activated JAK activates the PI3K/Akt/mTOR signal pathway, which induces an inflammatory response and is involved in the pathogenesis of PCM (23, 24).

Figure 2

Possible mechanisms for the role of T lymphocytes in GLM and PCM. Inducible factors such as stagnant ductal secretions or external collisions can lead to local mammary epithelial cell damage, and autoantigens in ductal secretions are taken up by APCs and processed into antigenic fragments. T cell receptors on the surface of naive CD4+ T cells and naive CD8+ T cells recognize MHC-II molecules and MHC-I molecules on the surface of APCs, respectively, and acquire antigenic fragments, while the activation of these two types of cells produces various immune cytokines or molecules. Inflammatory factors produced by Th cell subsets subsequently activate cellular or humoral immunity, and CD8+ T cells act on target cells infected with antigens through the surface FasL receptor to cause target cells to lyse. APC, antigen-presenting cell; TCR, T cell receptor; FasL, Fas ligand.

Figure 3

Pathological mechanisms common to GLM and PCM. There is activation of the complement system in GLM and PCM. On the one hand, complement activation can lead to the formation of membrane attack complex (MAC), which is located on the epithelial membrane cells and leads to the damage of mammary ductal epithelial cells (127); on the other hand, there are elevated levels of C3/C3a-C3aR and C5/C5a-C5aR1 in their tissue samples, and the intercellular adhesion factors (ICAM-1, E-selectin, and P-selectin) are elevated, which can promote inflammatory cell adhesion and aggregation (128).

Figure 4

Crosstalk between other immune factors and NPM (GLM and PCM). PRL, prolactin; HDL, high-density lipoprotein; TLR, Toll-like receptor; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-κB; PI3K/AKT/mTOR, phosphatidylinositol 3- kinase/protein kinase B/mammalian target of rapamycin; NLRP3, NOD-like receptor protein 3.