Properdin

Properdin (factor P) is a positive regulator of the alternative signaling pathway. Chemically, it is a plasma-derived glycoprotein produced mainly by leukocytes. Properdin positively regulates the activity of the "alternative complement signaling pathway" by stabilizing C3 and C5 convertases and initiating AP.

Promotion of complement activity by properdin leads to changes in the cellular microenvironment that contribute to innate and adaptive immune responses, including production of proinflammatory cytokines, infiltration of immune cells, maturation of antigen-presenting cells, and tissue damage. Properdin inhibits factor H.

In particular, a deficiency of properdin is associated with increased susceptibility to Neisseria species (Janeway et al. 2001).

Biochemically, properdin is a glycoprotein synthesized as a single-chain molecule of 469 amino acids that contains a 27-amino acid leader sequence leading to 442 amino acids in the mature protein. Each properdin monomer consists of six complete thrombospondin type 1 repeat (TSR) domains. The TSR domains are designated TSR1-6 and a truncated N-terminal domain (TSR0) that contains conserved key residues. Properdin is post-translated by C-mannosylation, O-fucosylation, N-glycosylation, and C-glycosylation.

Properdin functions in immune responses: Properdin can promote activation of the alternative signaling pathway on platelets by acting as either an initiator or a convertase stabilizer, leading to C5a formation and C5aR-mediated neutrophil activation, upregulation of CR3 expression, which promotes platelet-granulocyte aggregate (PGA) formation, and release of properdin into the microenvironment.

Properdin can bind directly to platelets and/or neutrophilic granulocytes, resulting in additional complement activation or convertase stabilization. C3b formed in the microenvironment may deposit on surfaces and serve as initial priming for additional amplification of the alternative pathway.

Neutrophils, neutrophil extracellular traps (NETs), and properdin. Complement components released by neutrophils, including properdin, factor B, and C3, deposit on NETs formed by neutrophils. The alternative signaling pathway is activated on NETs, resulting in the deposition of C5b-9. (C) Properdin and dendritic cells (DCs). Properdin secretion by dendritic cells (DCs) is inhibited by IFN-gamma.

Factor H production by DCs is enhanced by IL-27 and IFN-γ. Inhibition of properdin reduces proliferation of CD4+ T cells, whereas inhibition of factor H increases proliferation of CD4+ T cells. (D) Properdin and natural killer (NK) cells. Properdin is recognized by the NKp46 receptor on NK cells and subsets of innate lymphoid cells (ILCs) 1 and 3 (not shown). This interaction leads to upregulation of Xcl1 expression (dashed line) and may also protect the host from Neisseria meningitidis infection.

The very rare properdin deficiency leads to the clinical picture of X-linked recessive inherited properdin deficiency (properdin deficiency, X-linked/OMIM: 312060).

Affected patients are susceptible to fulminant meningococcal infections.

1. Chen JY et al. (2018) Properdin: A multifaceted molecule involved in inflammation and diseases. Molecular immunology 102: 58-72.
2. Chen JY et al. (2018) A multifaceted molecule involved in inflammation and diseases. Mol Immunol102:58-72.
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7. Janeway CA et al (2001) Immunobiology: the immune system in health and disease. (5th ed.) New York: Garland Publ p 50-53.