Inflammasomes are molecular complexes activated by infection and cell stress, responsible for activating caspase-1 that subsequently facilitates IL-1b processing and cell death. We have discovered inflammasome deficiencies in the autoimmune NZB mouse strain. NZB has a point mutation leading to loss of expression of inflammasome initiator NLRP3, and is also deficient in AIM2 inflammasome function. NZB mice develop anti-erythrocyte antibodies and haemolytic anaemia, and also anti-nuclear antibodies typical of lupus. We hypothesise that the inflammasome deficiencies in NZB alter the interaction of the host with both microflora and pathogens, promoting prolonged production of cytokines, which contribute to loss of tolerance. A more aggressive model of lupus is the first cross progeny of NZB and NZW mice, which develop severe lupus nephritis. Here we have investigated AIM2 and NLRP3 inflammasome function in cells from NZB, NZW and NZB/W F1 mice. Outputs such as cell death, ASC speck formation and IL-1β processing were measured in response AIM2 inflammasome stimuli, electroporated DNA and mouse cytomegalovirus (MCMV) infection and the NLRP3 inflammasome stimuli nigericin, ATP, alum and Candida albicans. The NZW parental strain showed strong inflammasome function. However, the NZB/W F1 mice still expressed enough p202 to have reduced AIM2 inflammasome responses. In parallel with AIM2 function, the complete deficiency of NLRP3 in NZB mice led to haploinsufficient expression of NLRP3 in cells from the F1 mice, and consequently function that was intermediate between NZB and NZW. Despite moderate deficiency in the F1 mice, both inflammasome systems were capable of giving substantial responses under conditions of high stimulus. The partial inflammasome deficiency in NZB/W F1 mice could contribute to the initiation of autoimmunity. However, with abundant self danger molecules as triggering stimuli later in disease, NLRP3 inflammasome may exacerbate kidney damage. This work highlights the complex role that inflammasomes could play in autoimmune disease.