Tolerating Aire - Out of the Thymus

The immune system protects us against infections but it must also tolerate the many different proteins that constitute our bodies. T lymphocytes of the immune system that react against the body’s own proteins could trigger autoimmunity, so they are usually deleted during their maturation in the thymus. A protein called Aire (Autoimmune regulator) turns on expression in the thymus of nearly 2,000 genes that are otherwise expressed in only a few organs and tissues, thereby exposing new T cells to these proteins and avoiding autoimmune disease. Indeed, mutations in Aire result in a broad autoimmunity against many organs and tissues. Previously, Aire was thought by many to be expressed only in the thymus.

Gardner and colleagues detected Aire in rare stromal (non-lymphoid) cells they called extrathymic Aire-expressing cells (eTACs) within the spleen, lymph nodes, and Peyer’s patches (nodes associated with the gut). These cells are located between the T and B cell areas of these organs but are highly mobile. Surprisingly, Aire turned on different genes in eTACs than were turned on in the thymus, suggesting that Aire expression in eTACs is not a ‘safety net’ for T cells that accidentally escaped the thymus but rather acts to delete additional autoreactive T cells. In eTACS, Aire turned on fewer than 200 genes, but several of these are suspected to be involved in autoimmunity, including desmoglein 1a (in pemphigous foliaceus) and the N-methyl-D-aspartate receptor 2C (in lupus). In an animal model of type 1 diabetes, eTACs expressing glucose-6-phosphate-related protein deleted T cells specific for this protein and prevented onset of this autoimmune disease (Fig. 2f shown, open squares represent mice expressing glucose-6-phosphatase-related Adig in eTACs).

These findings suggest that manipulating eTACs is a promising approach to therapy for autoimmune disease. Comparing eTACs in healthy people and autoimmune patients might also help identify deficiencies that can be corrected to prevent or ameliorate disease.

Gardner JM, Devoss JJ, Friedman RS, Wong DJ, Tan YX, Zhou X, Johannes KP, Su MA, Chang HY, Krummel MF, Anderson MS. Deletional tolerance mediated by extrathymic Aire-expressing cells. Science. 2008 Aug 8;321(5890):843-7.

Homozygosity mapping: Autism in the family

Most genes identified in genome-wide analyses contribute only modestly to disease risk or protection, with already low relative risks changed only ~20%, and taken together probably contribute to a minority of disease cases. Morrow and colleagues took a different approach, believing that analyzing individual families might reveal higher-risk genes for autism spectrum disorders (ASDs). They noted that offspring of first-cousins have twice as many neurological birth defects, including ASDs.

They also noted that a significant involvement of autosomal recessive genes would be 'signaled' by change in the male-to-female ratio (because the M:F ratio is typically 1:1 for autosomal recessive traits vs. male-dominant ASD). Indeed, among the 104 families recruited for the study, the M:F ratio was 2.6 for the offspring of the 88 consanguineous families (cousins) vs. 7.4 for the non-consanguineous.

They genotyped using arrays of SNPs and BACs, the latter validated for comparative genomic hybridization (CGH) detection of copy number variation (CNV) due to deletions, etc. Few de novo (not inherited) CNVs were detected. Large deletions on both DNA strands of the affected child (homozygous), and one strand of each parent (hemizygous), were found in 5 of the 78 consanguineous families but not among any of the other ~400 ASD cases or ~2,400 controls. In the figure (from Figure 1C), the SNPs spanning a large deletion in the AU-3100 pedigree is shown: the parents 3103 & 3104 (top and second) are hemizygous as is one child (3102, third down) but the other child, 3101 (bottom), who is homozygous for the deleted chromosome, has autism and seizures.

The investigators were surprised to find 3 genes linked to the 2 largest deletions were previously identified as being regulated by neural activity, and thus candidates for involvement with learning. Mutations in one of these genes, NHE9, were detected in non-consanguineous families and associated with additional neurological disorders (epilepsy) and learning delays (language acquisition).

EM Morrow et al. Identifying autism loci and genes by tracing recent shared ancestry. Science. 2008 Jul 11;321(5886):218-23.