| 1. |
- Hässler, Signe, et al.
(författare)
-
Aire deficient mice develop hematopoetic irregularities and marginal zone B cell lymphoma
- 2006
-
Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 108:6, s. 1941-1948
-
Tidskriftsartikel (refereegranskat)abstract
- Autoimmune polyendocrine syndrome type I (APS I) is an inherited recessive disorder with a progressive immunological destruction of many tissues including the adrenal cortex, the parathyroid glands, and the gonads. APS I is caused by mutations in the AIRE gene (autoimmune regulator), expressed in cells of the thymus and spleen, suggesting a role in central and peripheral tolerance. Aire(-/-) mice replicate the autoimmune features of APS I patients with the presence of multiple autoantibodies and lymphocytic infiltrates in various tissues, but young mice appear clinically healthy. We here report the investigation of 15- to 24-month-old Aire(-/-) mice. We did not observe any endocrinological abnormalities, nor did sera from these mice recognize known APS I autoantigens. Interestingly, however, there was a high frequency of marginal zone B-cell lymphoma in Aire(-/-) mice and liver infiltrates of B cells, suggesting chronic antigen exposure and exaggerated activation. Furthermore, increased numbers of monocytes in blood were identified as well as augmented numbers of metallophilic macrophages in the spleen. We propose that Aire, in addition to its function in the thymus, also has a peripheral regulatory role by controlling the development of antigen-presenting cells (APCs) and marginal zone B-cell activation.
|
|
| 2. |
- Brännström, Johan, et al.
(författare)
-
Defect internalization and tyrosine kinase activation in Aire deficient antigen presenting cells exposed to Candida albicans antigens
- 2006
-
Ingår i: Clinical Immunology. - : Elsevier BV. - 1521-6616 .- 1521-7035. ; 121:3, s. 265-273
-
Tidskriftsartikel (refereegranskat)abstract
- Patients with Autoimmune polyendocrine syndrome type I (APS I) present with multiple endocrine failures due to organ-specific autoimmune disease, thought to be T-cell-mediated. Paradoxically, APS I patients suffer from chronic mucocutaneous candidiasis. The mutated gene has been identified as the Autoimmune regulator (AIRE). Aire is expressed in medullary epithelial cells of the thymus and in antigen presenting cells in the periphery. T cells from Aire deficient mice and men displayed an enhanced proliferative response against Candida antigen in vitro, suggesting that Aire deficient T cells are competent in recognizing Candida albicans. In contrast, monocytes from APS I patients displayed a decreased and delayed internalization of zymosan. Furthermore, Candida antigen activated monocytes from APS I patients show decreased and altered phoshotyrosine kinase activation. In conclusion, Aire deficient APCs have a defect receptor mediated internalization of Candida which affects kinase activation, likely altering the innate Candida immune response.
|
|
| 3. |
- Lindh, Emma, et al.
(författare)
-
Autoimmunity and cystatin SA1 deficiency behind chronic mucocutaneous candidiasis in autoimmune polyendocrine syndrome type 1
- 2013
-
Ingår i: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411 .- 1095-9157. ; 42, s. 1-6
-
Tidskriftsartikel (refereegranskat)abstract
- Patients with the monogenic disease autoimmune polyendocrine syndrome type I (APSI) develop autoimmunity against multiple endocrine organs and suffer from chronic mucocutaneous candidiasis (CMC), a paradoxical complication with an unknown mechanism. We report here that saliva from APSI patients with CMC is defective in inhibiting growth of Candida albicans in vitro and show reduced levels of a salivary protein identified as cystatin SA1. In contrast, APSI patients without CMC express salivary cystatin SA1 and can inhibit C. albicans to the same extent as healthy controls. We evaluated the anti-fungal activity of cystatin SA1 and found that synthesized full length cystatin SA1 efficiently inhibits growth of C. albicans in vitro. Moreover, APSI patients exhibit salivary IgA autoantibodies recognizing myosin-9, a protein expressed in the salivary glands, thus linking autoimmunity to cystatin SA1 deficiency and CMC. This data suggests an autoimmune mechanism behind CMC in APSI and provides rationale for evaluating cystatin SA1 in antifungal therapy.
|
|
