Small heat-shock proteins are conserved molecular entities present in all mammalian cells. They have historically been studied in the context of being intracellular molecular chaperones that are constitutively expressed, with a capacity to be induced by cellular stress, in order to promote and remediate protein folding. More recently however, growing evidence suggests that the action of small heat-shock proteins is not limited to protein folding but also extends to a wider range of important cellular roles. Of the 11 small heat-shock proteins that are expressed in mammalian cells, only 4, HSPB1, HSPB5, HSPB6 and HSPB8, are expressed in the central nervous system (CNS). The role of these small heat-shock proteins in the CNS is thought to be protective as they show widespread upregulation during several neurological conditions. Confoundingly however, studies from R6/2 animal models of Huntington’s disease show a selective reduced expression of HSPB5 in these animals, raising pertinent questions as to whether this reduction is cause or effect of the condition. Here, we have investigated whether reduced expression of HSPB5 has a detrimental effect, focussing specifically on HSPB5’s proposed immune modulatory role. Using mice inoculated with S. typhimurium, we found that, in our hands, mice lacking HSPB5 did not appear to be phenotypically different from wild type animals and equally, the reduced expression of HSPB5 did not exacerbate systemic inflammation or potentiate disease progression. Furthermore, to investigate HSPB5’s role in the CNS, we inoculated animals with ME7 Prion and also found that deficiency in HSPB5 did not alter phenotype or behaviour and did not negatively influence disease progression. Lastly, we investigated whether the reduced expression of HSPB5 as observed in R6/2 animals was reciprocated in humans. Our findings show that in humans disease, there is no reduction of HSPB5. Our findings suggests that in C57BL/6 animals, HSPB5 does not appear to have an immune modulatory role; they also highlight how data obtained from animal models should be taken tentatively.