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Microbes & Immunity Big data and DNN-based DTI model in CHP

Interleukin 6 primarily promotes Th17 differentiation of T-cells. In healthy lung tissues, the expression of
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in the presence of TGF-β. It can also create a pro- IL2 and IL12 are typically low or undetectable, whereas,
inflammatory environment that indirectly supports Th1 in CHP lung slice cells, their expression is elevated. In
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responses. In addition, IL-21 can directly enhance Th1 conjunction with IL2, it can amplify the inflammatory
responses by increasing interferon (IFN)-γ production. This response by increasing the production of other cytokines
can boost the ability of Th1 cells to activate macrophages and chemokines, leading to the recruitment and activation
and enhance their antimicrobial activities. The presence of additional immune cells. Moreover, IL12 induces the
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of IL-6 and IL-21 can help balance different aspects of the production of IFN-γ, which, in turn, can stimulate the
immune response. IL-6 can promote a pro-inflammatory production of TNF-α by various immune cells. This creates
environment, while IL-21 can support both humoral and a positive feedback loop that amplifies the Th1 response
cell-mediated immunity by acting on various immune and enhances the ability to combat intracellular pathogens.
cells, including Th1 cells. The binding of IL-6 to its receptor The synergy between target genes IL12 and IL2 enhances
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induces the dimerization of glycoprotein gp130, bringing the overall immune response within the granuloma. IL12
associated JAK1 and JAK2 into proximity, which allows drives the initial Th1 response and macrophage activation,
for trans-phosphorylation and activation of JAK1 and while IL2 sustains T-cell proliferation and activation,
JAK2. Similarly, the binding of IL-21 to its receptor induces ensuring that the granuloma remains an effective barrier
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the association of JAK1 and JAK3, allowing for trans- against the pathogen. This crosstalk suggests a self-
phosphorylation and activation of JAK1 and JAK3. These sustaining inflammatory loop, wherein the activation of
phosphorylated tyrosines serve as docking sites for signal these pathways upregulates CCL2 expression, and CCL2, in
transducers and activators of transcription (STAT) proteins, turn, potentiates the activation of these signaling cascades,
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particularly STAT3. In the nucleus, phosphorylated STATs exacerbating the inflammatory milieu. The interaction
act as TF to regulate the expression of target genes involved between CCL2 and its receptor, CCR2, on lung fibroblasts
in immune cell proliferation, differentiation, and function. has been shown to induce their migration, proliferation,
Activated STAT3 then translocates to the nucleus and and differentiation into myofibroblasts, which are key
promotes the expression of TF retinoic acid-related orphan mediators of the fibrotic process. 59
receptor (ROR)γt and RORα. Once expressed, TF RORγt In summary, compared to healthy control lung tissues,
and RORα directly regulate the transcription of Th17- hypersensitivity pneumonitis lung tissues show increased
specific genes, including IL17A, IL17F, and IL22. These expression of IL2 and IL12. The chemokine CCL2 interacts
target genes are key cytokines involved in the defense against with target genes IL2 and IL12 synergistically to regulate
extracellular pathogens, the promotion of inflammation, immune responses and inflammation, contribute to the
the regulation of fibrosis, and the direct killing or inhibition formation of granulomatous lesions, and promote fibrotic
of pathogen growth. This enhances the first line of defense remodeling through TNF-α and IFN-γ. Targeting the
at mucosal surfaces. 69 CCL2/CCR2 axis represents a promising therapeutic
strategy for modulating the aberrant inflammatory and
Furthermore, CCL2 has been implicated in the
formation and maintenance of granulomatous lesions, a fibrotic processes underlying CHP symptoms.
hallmark of CHP pathology. Th1 cells also produce IFN-γ, 3.4.2. The role of cytokine chemokine (C-C motif)
which works synergistically with TNF-α to enhance the ligand 20-cytokine chemokine (C-C motif) receptor 6
activation and microbicidal activity of macrophages. in immune response and pathogenesis of CHP
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TNF-α promotes the expression of adhesion molecules on
endothelial cells, facilitating the recruitment of leukocytes Organic microbes such as Candida albicans, Mycobacterium
to infection or inflammation sites. This enhances the avium, and Saccharopolyspora rectivirgula are associated
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local immune response, as this combination is particularly with CCL20 production and immune cell recruitment.
Their role in CHP could involve the recruitment of CCR6
effective in combating intracellular pathogens. The immune cells, leading to sustained lung inflammation
recruited monocytes and macrophages, along with other and fibrosis, which are characteristic features of CHP. In
inflammatory cells, aggregate and form non-caseating Figure 4, CD4 effector Th17 cells, influenced by the CCL20-
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granulomas, perpetuating the local release of cytokines, CCR6 chemotaxis, play a crucial role in immune responses
chemokines, and proteolytic enzymes, leading to the to mucosal surface infections. They are also associated
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progressive destruction of lung architecture. 78
with the development of various diseases, including
Subsequently, TNF-α and target genes IL2 and IL12 asthma, hypersensitivity pneumonitis, and autoimmune
can work together through the phosphorylated TF STAT4 diseases, such as rheumatoid arthritis. Chemokine CCR6
and STAT5 to enhance the activation and proliferation directs the migration of CD4 T-cells to inflammation sites
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Volume 2 Issue 2 (2025) 98 doi: 10.36922/mi.4620