The episodic autoinflammatory diseases Muckle–Wells syndrome and familial cold autoinflammatory syndrome (FCAS) are clearly linked to the inappropriate stimulation of inflammation, because they are due to mutations in NLRP3, a component of the ‘inflammasome’ that normally senses cell damage and stress as a result of infection (see Section 39). The mutations lead to the activation of NLRP3 in the absence of such stimuli and the unregulated production of proinflammatory cytokines. Patients with these dominantly inherited syndromes present with episodes of fever—which is induced by exposure to cold in the case of FCAS—as well as urticarial rash, joint pains, and conjunctivitis. Mutations in NLRP3 are also associated with the autoinflammatory disorder chronic infantile neurologic cutaneous and articular syndrome (CINCA), in which short, recurrent fever episodes are common, although severe arthropathic, neurologic, and dermatologic symptoms predominate. Both pyrin and NLRP3 are predominantly expressed in leukocytes and in cells that act as innate barriers to pathogens, such as intestinal epithelial cells. The stimuli that modulate pyrin and related molecules include inflammatory cytokines and stressrelated changes in cells. Indeed, Muckle–Wells syndrome responds dramatically to the drug anakinra, an antagonist of the receptor for IL1.
13-17 Hematopoietic stem cell transplantation or gene therapy can be useful to correct genetic defects.
It is frequently possible to correct the defects in lymphocyte development that lead to SCID and some other immunodeficiency phenotypes by replacing the defective component, generally by hematopoietic stem cell (HSC) transplantation (see Section 1536). The main difficulties in these therapies result from human leukocyte antigen (HLA) polymorphism. To be useful, the graft must share some HLA alleles with the host. As we learned in Section 821, the HLA alleles expressed by the thymic epithelium determine which T cells can be positively selected. When HSCs are used to restore immune function to individuals with a normal thymic stroma, both the T cells and the antigenpresenting cells are derived from the graft. Therefore, unless the graft shares at least some HLA alleles with the recipient, the T cells that are selected on host thymic epithelium cannot be activated by graftderived antigenpresenting cells (Fig. 13.15).
MHCb-restricted T cells can be activated by MHCa×b APC, and recognize infected MHCb cells Donor cells undergo selection on MHCb in the recipient thymus Hematopoietic stem cell transplant. One MHC allele shared MHCa×bmacrophageAPCMHCbTcells
Fig. 13.15 The donor and the recipient of a hematopoietic stem cell (HSC) graft must share at least some MHC molecules to restore immune function.
an HSC transplant from a genetically different donor is illustrated in which the donor marrow cells share some MHC molecules with the recipient. the shared MHC type is designated ‘b’ and illustrated in blue; the MHC type of the donor HSCs that is not shared is designated ‘a’ and shown in yellow. in the recipient, developing donor lymphocytes are positively selected on MHCb on thymic epithelial cells and negatively selected by the recipient’s stromal epithelial cells and at the corticomedullary junction by encounter with dendritic cells derived from both the donor HSCs and residual recipient dendritic cells. the negatively selected cells are shown as apoptotic cells. the donor-derived antigen-presenting cells (aPCs) in the periphery can activate t cells that recognize MHCb molecules; the activated t cells can then recognize the recipient’s infected MHCbbearing cells.
Host-versus-graft response. Graft failure