Table 3.

Summary of Paradoxical Cryptococcal-IRIS pathogenesis framework [19].

Phase	Immunologic Activity	Evidence in CM-IRIS Patients
Before ART	Paucity of appropriate inflammation for cryptococcosis and/or	↓ TNF-α, G-CSF, GM-CSF, VEGF in serum ↓ IFN-γ, G-CSF, TNF-α, IL-6 in CSF [21, 36]
	Inappropriate (Th2) responses resulting in:	↑IL-4 pre-ART
	Poor antigen clearance, pre-ART	Similar CSF CRAG at initial infection [36] Higher CRAG pre-ART
	Elevated CSF chemokine expression	↑Expression of CCL2, CCL3 in CSF[71]
After Starting ART	Increasing proinflammatory signaling from antigen presenting cells (APCs) due to persisting antigen burden and failure to clear antigen	↑ IL-6 from macrophages [72] then downstream ↑ CRP production; ↑ IL-7 from APCs
	Secondary activation of coagulation cascade	↑ D-dimer
At IRIS	Effective response of innate and adaptive immune systems	Th1 ↑IFN-γ, VEGF; TH17 ↑ IL-17 Innate: ↑ IL-8, G-CSF, GM-CSF ± Elevated CSF White blood cells ± Elevated CSF Protein Negative CSF culture ↑ IL-6+, TNF-α+ monocytes[73*]
	Activation of coagulation cascade	↑ D-dimer
	Neuronal cell activation and damage	↑ CSF FGF-2
	Aberrant innate cell trafficking	Trafficking of pro-inflammatory monocytes and CD4+ T cells into CSF [28].

Abbreviations: APC- Antigen presenting cell; IL- Interleukin; CRP- C reactive protein; IFN- Interferon; CSF- Cerebrospinal fluid; TNF- Tumor necrosis factor; CCL- C-C chemokine; ART- Antiretroviral Therapy; GM-CSF- Granulocyte macrophage colony stimulating factor; TH- T helper; CRAG- Cryptococcal Antigen; FGF-Fibroblast growth factor.