A possible pivotal role for transglutaminase 2 in the pathophysiology of cutaneous amyloidosis

MR Namazi

 Department of Dermatology, Wake-Forest University Baptist Medical Center, Winston-Salem, North Carolina, USA; Shiraz University of Medical Sciences, Shiraz, Iran,

Correspondence Address:
M R Namazi
Dermatology Department, Wake-Forest University Baptist Medical Center, Winston-Salem, North Carolina 27157, USA

Sir,

Amyloidosis is a generic term that signifies the abnormal extracellular tissue deposition of one of a family of biochemically unrelated proteins that share certain characteristic staining properties, including apple-green birefringence of Congo red-stained preparations viewed under polarizing light. ^[1],[2]

As a term, ′amyloid′ was used historically to define proteins that shared similar microscopic characteristics and affinity for certain stains. The various diseases characterized by deposition of ′amyloid′ proteins are similarly heterogeneous but have in common the deposits of fibrillar proteins characterized as ′amyloid′ in the dermis. In nodular localized cutaneous amyloidosis, the amyloid is believed to be derived from local plasma cells; in contrast to lichenoid or macular amyloidosis, which have keratinocyte-derived amyloid. ^[1],[2] Amyloid deposits in macular and lichen amyloidosis bind to anti-keratin antibodies and contain sulfhydryl groups, pointing to altered keratin as a source for these deposits. There is no difference in staining characteristics of cytokeratins between macular amyloidosis and lichen amyloidosis. ^[3] Some argue that the deposition of amyloid in macular and lichen amyloidosis may be the result of frequent itching and scratching. ^[4] The concept has arisen of focal epidermal damage and filamentous degeneration of keratinocytes, followed by apoptosis and conversion of filamentous masses (colloid bodies) into amyloid material in the papillary dermis, perhaps with a contribution from the dermal-epidermal junction. ^[5]

It has been proposed that in lichenoid and macular amyloidosis, specific immunologic tolerance to the presence of keratinocyte-derived apoptotic bodies in the papillary dermis favors their transformation into amyloid by macrophages or fibroblasts; whereas in lichen planus, an autoimmune disorder, a brisk inflammatory response ensures their removal. ^[6]

Transglutaminase 2 (TG2) is a unique member of an enzyme family (EC 2.3.3.13) because in addition to its primary enzymatic activity of Ca ²⁺ -dependent transamidation of polypeptide chains through their glutamine and lysine residues (or through polyamines), it also binds GTP (which blocks transamidation) and may act as a G protein. It is often up-regulated in cells undergoing apoptosis. In addition, another important role is attributed to TG2: the prevention of tissue injury, inflammation, and autoimmunity once the apoptosis has already been initiated. This function of TG2 is partially achieved by being expressed and activated also in macrophages digesting apoptotic cells and mediating a crosstalk between dying and phagocytic cells. Generally from the in vivo results obtained in some laboratories, it has been proposed that the most important role of TG2 in vivo is to ensure that apoptosis is finished without causing inflammation necrosis and apparent tissue injury. Besides facilitating apoptosis, induction of TG2, and enhancing phagocytosis, TGFβ was shown to be required for the proper down-regulation of pro-inflammatory cytokine production in macrophages as well. If, however, necrosis still occurs, TG2 promotes both tissue stability and repair. In TG2−/− animals, all these anti-inflammatory actions are compromised, which results in the appearance of inflammatory cells at the apoptotic sites in the short term and autoimmunity in the long term. ^[7],[8]

Moreover, it merits noting that transglutaminase is suggested to play a role in the pathogenesis of Dutch-type hereditary amyloidosis and Alzheimer′s disease by cross-linking proteins into insoluble polymers. ^[9]

Given the above facts altogether, couldn′t TG2 be involved in the pathogenesis of macular and lichen amyloidosis through promotion of keratinocyte apoptosis, facilitating the ingestion of apoptotic cells by macrophages, inhibiting inflammation, and cross-linking keratinocytic proteins to produce amyloid?

1.	Miethke MS, Raugi GJ. Amyloidosis, nodular localized cutaneous. In: e-medicine. Available from: http://www.emedicine.com/derm/topic17.htm. Last accessed: 23/02/08 [Google Scholar]
2.	Breathnach SM. Amyloid and amyloidosis. J Am Acad Dermatol 1988;18:1-16. [Google Scholar]
3.	Apaydin R, Gürbüz Y, Bayramgürler D, Müezzinoglu B, Bilen N. Cytokeratin expression in lichen amyloidosus and macular amyloidosis. J Eur Acad Dermatol Venereol 2004;18:305-9. [Google Scholar]
4.	Weyers W, Weyers I, Bonczkowitz M, Diaz-Cascajo C, Schill WB. Lichen amyloidosus: A consequence of scratching. J Am Acad Dermatol 1997;37:923-8. [Google Scholar]
5.	Chang YT, Wong CK, Chow KC, Tsai CH. Apoptosis in primary cutaneous amyloidosis. Br J Dermatol 1999;140:210-5. [Google Scholar]
6.	Breathnach SM. Amyloidosis of the skin. In: Freedberg IM, Eisen AZ, Wolff K, Austen KF, Glodsmith LA, Katz SI, editors. Fitzpatrick's dermatology in general medicine. Vol. 2, Chapter 148. 6 th ed. New York: McGraw-Hill; 2003. p. 1428-35. th ed. New York: McGraw-Hill; 2003. p. 1428-35.'>[Google Scholar]
7.	Fιsüs L, Szondy Z. Transglutaminase 2 in the balance of cell death and survival. FEBS Lett 2005;579:3297-302. [Google Scholar]
8.	Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 1998;101:890-8. [Google Scholar]
9.	Dudek SM, Johnson GV. Transglutaminase facilitates the formation of polymers of the beta-amyloid peptide. Brain Res 1994;651:129-33. [Google Scholar]