BACKGROUNDThe hygiene hypothesis proposed in 1989 expresses that allergic and infectious diseases are inversely related. Accordingly, it has been demonstrated that infection with some microorganisms such as parasites and helminths can provide a potential immunity and prevent the onset of some life-threatening autoimmune diseases like systemic lupus erythematosus (SLE). Therefore, in this comprehensive study, we systematically reviewed and discussed the use of live parasites or parasitic products in the treatment of mouse models of SLE.METHODSThe present systematic review was performed using the following search terms: ("systemic lupus erythematosus" OR "SLE" OR "lupus") AND ("parasite" OR "protozoa" OR "helminths" OR "worms" OR "helminth" OR "worm") in PubMed, Scopus, and Web of Science online databases. We included studies reporting the effect of any intervention using parasites or parasitic-based products on animal models of SLE, which were published until January 20th, 2021 without any language or date restrictions. For each included study, we extracted the authors' names, publication year, type of animal, number of groups, types of intervention, sample size, changes in immunologic cells, auto-Abs, cytokines, and blood cells count, urine analysis, histological analysis of kidney/spleen/liver, outcome and survival. (PROSPERO CRD42020160460).RESULTSA total of 17 eligible articles were included in this systematic review. Sixteen out of the 17 studies reported immunomodulating changes in immunologic cells, cytokines, and/or auto-Abs in mouse models of SLE after using parasitic interventions compared to not-infected or control groups. Moreover, 14 studies reported decreased level of proteinuria and/or favorable kidney, liver, or spleen histological changes.CONCLUSIONIn conclusion, we have demonstrated that parasites like Hymenolepis microstoma, TPC and ES-62 from Acanthocheilonema viteae, Plasmodium chabaudi, Schistosoma mansoni, and Toxoplasma gondii have favorable immunomodulating effects on SLE outcomes in lupus-prone mice.