HLA associations, somatic loss of HLA expression, and clinical outcomes in immune aplastic anemia

Abstract

Immune aplastic anemia (AA) features somatic loss of HLA class I allele expression on bone marrow cells, consistent with a mechanism of escape from T cell-mediated destruction of hematopoietic stem and progenitor cells. The clinical significance of HLA abnormalities has not been well characterized. We examined somatic loss of HLA class I alleles, and correlated HLA loss and mutation-associated HLA genotypes with clinical presentation and outcomes after immunosuppressive therapy in 544 AA patients. HLA class I allele loss was detected in 92 (22%) of the 412 patients tested, in whom there were 393 somatic HLA gene mutations and 40 instances of loss of heterozygosity. Most frequently affected was HLA-B*14:02, followed by HLA-A*02:01, HLA-B*40:02, HLA-B*08:01, and HLA-B*07:02. HLA-B*14:02, HLA-B*40:02, and HLA-B*07:02 were also overrepresented in AA. High-risk clonal evolution was correlated with HLA loss, HLA-B*14:02 genotype, and older age, which yielded a valid prediction model. In two patients, we traced monosomy 7 clonal evolution from preexisting clones harboring somatic mutations in HLA-A*02:01 and HLA-B*40:02. Loss of HLA-B*40:02 correlated with higher blood counts. HLA-B*07:02 and HLA-B*40:01 genotypes and their loss correlated with late onset of AA. Our results suggest the presence of specific immune mechanisms of molecular pathogenesis with clinical implications. HLA genotyping and screening for HLA loss may be of value in the management of immune AA. This study was registered at clinicaltrials.gov as NCT00001964, NCT00061360, NCT00195624, NCT00260689, NCT00944749, NCT01193283, and NCT01623167.

Genome‐wide uniparental disomy as a mechanism of immune escape in acquired aplastic anaemia

“…The patient inherited from her mother two class I risk HLA alleles, A*33:01 and B*14:02 (Table 1). 2,3 GMA of the patient's skin biopsy showed a normal genomic complement, with no evidence of mosaicism for GW-UPD or 6p CN-LOH. (Figure 1A,B), demonstrating the somatic origin of 6p CN-LOH and GW-UPD.…”

“…Loss of function of human leucocyte antigen (HLA) occurs due to somatic gene mutations and copy-number-neutral loss of heterozygosity (CN-LOH), and HLA loss in acquired aplastic anaemia (aAA) is non-randomly associated with specific HLA alleles (risk alleles). [1][2][3] Herein we report a novel mechanism (genome-wide uniparental disomy, GW-UPD) of immune escape in a patient with aAA with two, in cis, class I HLA risk alleles.…”

“…The probability of finding loss of HLA class I function due to somatic mutations in patients with aAA is non-random with respect to HLA class I haplotype. [1][2][3][4] The basis of the correlation between HLA haplotype and risk of somatic loss of HLA is uncertain. Notably, the patient reported herein had two risk alleles in cis (Table 1) that are not known to be in linkage disequilibrium.…”

“…Approximately 15%-20% of patients with aAA have evidence of loss of function of HLA class I due to somatic gene mutation or 6p CN-LOH (or both) affecting various proportions of haematopoietic cells. [1][2][3] In the setting of aAA, such mutated HSPCs escape immune attack because they cannot present the putative target antigen. The patient presented herein, had two populations of cells with 6p CN-LOH.…”

Pathogenicity and impact of HLA class I alleles in aplastic anemia patients of different ethnicities

“…Given the tremendous diversity of HLA alleles across racial and ethnic groups, is AA in patients of different ethnicities mediated through the same alleles and autoantigen(s)? Finally, while there has been a growing body of literature on the clinical predictive value of having somatic clones with HLA allele loss (7,11,(15)(16)(17)(18)(19), the significance of the patients' HLA Class I repertoire for development of AA and the impact that specific risk alleles play for the patients' clinical course still remain poorly understood.…”