DESMOGLEIN-4 DEFICIENCY PROMOTES ANTI-DNA AUTOANTIBODIES IN RESPONSE TO IMIQUIMOD

MICHEL LARA, MC; SANCHEZ B; VIRUEL, L.B.; PITTON J; MOISO A; SOAJE M.; PIETROBON EO; INOCENTI BADANO C; VALDEZ SR; MACKERN-OBERTI JP

San Luis

Congreso; LXXI ANNUAL MEETING OF THE ARGENTINEAN SOCIETY OF IMMUNOLOGY (SAI); 2023

Sociedad Argentina de Inmunología

Desmogleins (Dsg) are transmembrane proteins involved in cell-cell junction.Keratinized epithelia, such as skin, expresses several forms of Dsg. Dsg4deficiency is associated with hair loss in humans, mice, and rats. Recently, wehave reported that topical administration of imiquimod (IMQ) to Dsg4 deficientrats exacerbates skin inflammation. Unfortunately, the role of Dsg4 in theinduction of IgG humoral immunity has not been addressed. Moreover, the roleof certain Dsg, such as Dsg4, in modulating lymphatic drainage in response tolocal inflammation has yet to be studied. Lastly, whether Dsg4 deficiency mayfavor autoimmune disease is entirely unknown. Our work aimed to determinewhether Dsg4 deficiency affects the induction of an antigen-specific immuneresponse and anti-DNA autoantibodies development in response to imiquimod.For this purpose, Dsg4 deficient Oncins France Colony A hairless/hairless (Dsg4null) and wild-type Sprague-Dawley (SD) rats were inoculated intradermally withOVA or PBS, and imiquimod cream was subsequently administered topically forthree consecutive days in dorsal skin. Two weeks later, serum samples wereobtained to determine OVA-specific IgG levels by ELISA assays. Additionally,Dsg4 null and SD rats were chronically administered thrice weekly for twelveweeks to evaluate the induction of anti-DNA antibodies. Surprisingly, Dsg4 nullrats showed lower OVA- specific IgG and IgG2a levels than the SD group. Bycontrast, Dsg4 null rats displayed higher IgG natural antibodies against thedinitrophenyl group but similar natural IgM anti-LPS levels compared to controlSD rats. When we evaluated brachial lymph node expansion after topicaladministration of IMQ we observed that Dsg4 null rats showed increased brachiallymph node weight compared to SD rats. Additionally, anti-DNA antibodies fromDsg4 null rats treated with IMQ chronically exhibited significantly higher levelsthan SD-treated rats. By contrast, spleens size and brachial lymph nodes fromchronically treated Dsg4 null and SD rats were enlarged similarly. These resultssuggest that Dsg4 may contribute to the induction of a specific humoral immuneresponse. Several mechanisms may be involved in the altered Ig response ofDsg4 null rats, including alterations in lymphatic drainage, keratinocyte-derivedcytokines, fine crosstalk between keratinocytes and dendritic cells, and germinalcenter reaction. Additionally, the higher induction of anti-DNA autoantibodiessuggests that Dsg4 deficiency unleashes an autoimmune susceptible condition.Although further investigations are necessary, our results suggest a novel role forDsg4 in supporting humoral immunity and immune tolerance under inflammatoryconditions.