Due to its strong association with Ankylosing Spondylitis and the other Spondyloarthropathies, the HLA-B27 family of alleles and, in particular, the ancestral HLA-B*2705, has been the object of numerous studies. More recently, some novel interesting features have emerged such as the ability of HLA-B27 to confer resistance to the progression of HIV infection and to promote a spontaneous CD8+ T cell-mediated viral clearance of HCV. The co-occurrence of these protective and pathogenic features suggests a common ground, i.e. to promote a more pronounced immune/inflammatory response leading to an effective clearance of some pathogens on one side and to autoimmunity on the other. This might be due to the antigen presenting properties and/or to the co-inheritance of gene variants that contribute to an altered homeostasis in case of microbial infections or tissue injury. The existence of conserved HLA haplotypes have since long been thought to result from a selective pressure by some pathogens that have edited the immune response genes. The peculiar distribution of the ancestor HLA-B*2705 along a latitude-dependent gradient and the opposite distribution of their variants have suggested a correlation with endemic malaria. In this respect, Sardinia, a small Mediterranean island plagued by malaria, represents an interesting laboratory since its population is enriched in conserved HLA haplotypes and several genetic studies have disclosed their correlation with infectious and autoimmune diseases.