Genetic Hearing Loss Associated With Autoinflammation.

Sensorineural hearing loss can result from dysfunction of the inner ear, auditory nerve, or auditory pathways in the central nervous system. Sensorineural hearing loss can be associated with age, exposure to ototoxic drugs or noise, or mutations in nuclear or mitochondrial genes. However, it is idiopathic in some patients. Although these disorders are mainly caused by dysfunction of the inner ear, little of the pathophysiology in sensorineural hearing loss is known due to inaccessibility of the living human inner ear for biopsy and pathological analysis. The inner ear has previously been thought of as an immune-privileged organ. We recently showed that a missense mutation of the NLRP3 gene is associated with autosomal-dominant sensorineural hearing loss with cochlear autoinflammation in two unrelated families. NLRP3 encodes the NLRP3 protein, a key component of the NLRP3 inflammasome that is expressed in immune cells, including monocytes and macrophages. Gain-of-function mutations of NLRP3 cause abnormal activation of the NLRP3 inflammasome leading to IL-1ß secretion in a spectrum of autosomal dominant systemic autoinflammatory phenotypes termed cryopyrin-associated periodic syndromes. The affected subjects of our two families demonstrated atypical phenotypes compared with those reported for subjects with cryopyrin-associated periodic syndromes. These observations led us to test the hypothesis that macrophage/monocyte-like cells in the cochlea can mediate local autoinflammation via activation of the NLRP3 inflammasome. The inflammasome can indeed be activated in macrophage/monocyte-like cells of the mouse cochlea, with secretion of IL-1ß. The macrophage/monocyte-like cells in the cochlea were also found to be associated with hearing loss in a Slc26a4-insufficient mouse model of human deafness. This review addresses our understanding of genetic hearing loss mediated by autoinflammation and macrophage/monocyte-like cells in the cochlea.

Interleukin-12-producing CD103+ CD11b- CD8+ dendritic cells are responsible for eliciting gut intraepithelial lymphocyte response against Encephalitozoon cuniculi.

Microsporidia, which belong to the kingdom Fungi, are important opportunistic pathogens in HIV-infected populations and organ transplant recipients that are often associated with a broad range of symptoms, such as diarrhea, nephritis, and encephalitis. Natural infection occurs via the oral route, and as a consequence, gut immunity plays an important role in restricting the dissemination of these pathogens. Studies from our laboratory have reported that the pathogens induce a rapid intraepithelial lymphocyte (IEL) response important for host protection. Although mucosal dendritic cells (DC) are likely involved in triggering an antigen-specific IEL response, the specific subset(s) responsible has yet to be identified. Toward this goal, we demonstrate a very important role for mucosal CD11b(-) CD8(+) DC in the initiation of an antigen-specific IEL in vivo. Effectively, after Encephalitozoon cuniculi infection, CD11b(-) CD8(+) DC were activated in the lamina propria (LP) and acquired the ability to process retinoic acid (RA). However, this subset did not produce interleukin 12 (IL-12) but upregulated CD103, which is essential for migration to the mesenteric lymph nodes (MLN). Interestingly, CD103(+) CD11b(-) CD8(+) DC in the MLN, in addition to processing RA, also secreted IL-12 and were responsible for gut imprinting specificity on mucosal CD8 T cells. To the best of our knowledge, this is the first report describing the importance of MLN CD103(+) CD11b(-) CD8(+) DC isolated from infected animals in the generation of an IEL response against a live pathogen.

Effector CD8 T cell immunity in microsporidial infection: a lone defense mechanism.

Microsporidia is a group of pathogens, which can pose severe risks to the immunocompromised population such as HIV-infected individuals. The expertise to diagnose these pathogens is limited and therefore their prevalence is believed to be much higher than what is currently known. In a mouse model of infections, it has been reported that CD8 T cells are the primary effector cells responsible for protecting the infected host. As the infection is acquired via per-oral route, CD8 T cells in the gut compartment apparently act as a first line of defense against the pathogens. Thus, generation of a robust CD8 T cell response that exhibits polyfunctional ability is critical for host survival. In this review, we describe the effector CD8 T cells generated during microsporidial infection and underline the factors that may be essential for the elicitation of protective immunity against this understudied but significant pathogen. Overall, this review will highlight the necessity for a better understanding of the development of the CD8 T cell response in gut associated lymphoid tissue (GALT) and provide some insights into therapies that may be used to restore defective CD8 T cell functionality in an immunocompromised situation.