Patients with Chronic Lymphocytic and Non-Hematologic Autoimmune Disorders Show Distinctive Clinical and Immune Alterations in Th17 and Treg Cells

Background:

Chronic lymphocytic leukemia (CLL) is marked by severe immune dysfunction, which results in an increased risk of autoimmune disorders (AID). While autoimmune cytopenia (AIC) has been extensively described in patients with CLL, the clinical characteristics and pathogenesis behind non-hematologic AID are poorly understood. However, there is some indication that T helper and T reg cells might be involved in the pathogenesis of several AIDs as well as in CLL progression. The aims of the present study are twofold: to analyze the prevalence of non-hematologic AID in patients with CLL and their clinical features; and second, to describe alterations in the T/NK cellular compartment in patients with CLL and non-hemic AID.

Methods:

We seek AID in a retrospective single-center series of 907 patients with a confirmed diagnosis of CLL. Clinical and biological characteristics were collected in patients with CLL; time to first treatment (TTFT) and overall survival (OS) were calculated. Blood samples were collected from untreated patients with CLL and AID, CLL without AID, and individuals with AID without CLL. T cell subpopulations [T-αβ (T helper CD4+, T helper subtypes (Th1, Th2, Th17, Treg), and T cytotoxic CD8+), T-γδ, exhausted T cells [HLA-DR+/PD1+ in CD4+ and CD8+], maturation profiles (T naïve, T central memory, T effector memory, T effector)], and NK cells were analyzed in peripheral blood samples.

Results:

After a median follow-up of 6.6 years (0.1-36.4), 99 out of 907 patients (10.9%) presented non-hematologic AID, 46 (5.1%) AIC, and 11 (1.2%) both AIC and non-hematologic AID. The most frequent non-hematologic AID were autoimmune hypothyroidism (n=46), psoriasis (n=23), rheumatic polymyalgia (n=8), rheumatoid arthritis (n=7), and pemphigus (n=5). Female sex (OR 1.7 (1.1-2.7); p=0.02) was the only risk factor of non-hematologic AID in CLL patients. Patients with CLL and non-hematologic AID had a significantly longer TTFT (13.8 vs 3.6 years; p<0.001) and OS (15.1 vs 9.9 years; p=0.005) than patients with CLL and AIC.

We further looked at the T/NK cell populations in patients with CLL with and without psoriasis, one of the most frequent AID found in this series; non-CLL individuals with psoriasis were included as a control. As expected, we found a heterogeneous composition of T/NK cells in samples from patients with CLL. Patients with stable CLL showed a higher rate of Th17 cells (2.7% vs 0.3%; p=0.002), and significantly lower counts of other T cell subpopulations including CD4+, CD8+, Th2, Treg, T-γδ, and HLA-DR+/PD1+ CD4+ and CD8+ cells, compared to those with progressive disease. Furthermore, we observed that patients with CLL and concomitant psoriasis showed a similar T/NK pattern to those with CLL stable without AID, except for the counts of Th17 and T reg cells that were significantly higher in CLL patients with AID [Th17 263 cells/mL vs 142 cells/mL (p=0.009); Treg 66 cells/mL vs 30 cells/mL (p=0.01)]. No differences in other T and NK cell populations were observed in patients with stable CLL with and without AID. In terms of prognosis, patients with CLL and psoriasis had significantly better prognosis compared to CLL without AID, the TTFT being at 15 years 65.7% vs 48.1% (p=0.04). When compared with individuals with psoriasis, the pattern of T cell populations including Th17 cells was similar to those patients with CLL and psoriasis except in T regs that were higher in the CLL population. Using an unsupervised hierarchical clustering including CLL with and without AID, we found a cluster exclusive of patients with CLL and psoriasis characterized by higher counts of Th17 and Treg cells and lower counts of T-CD8+ and T-γδ cells.

Conclusion:

In the present study, 10.9% of patients with CLL presented non-hematologic AID. The association with CLL and non-hemic AID was related to a good prognosis. In the population with CLL and psoriasis, we showed a lower risk of progression compared to the whole CLL population without AID. The expansion of Th17 and Treg cells in patients with CLL and psoriasis could explain the lower risk of leukemic progression. Functional studies are ongoing.