Researchers at Brigham and Women’s Hospital have demonstrated that for patients with unusual autoimmune or inflammatory conditions, cellular and transcriptomic immunophenotyping can serve as complementary diagnostic tools and guide treatment decisions.

Alisa A. Mueller, MD, PhD, Takanori Sasaki, MD, PhD, and Deepak A. Rao, MD, PhD, rheumatologists in the Division of Rheumatology, Inflammation and Immunity at the Brigham, and colleagues published their findings as a research letter in The Journal of Clinical Investigation.

Methods

The researchers evaluated peripheral blood mononuclear cells (PBMCs) from 16 patients in Harvard University’s Undiagnosed Diseases Network site who were suspected of having an immune-mediated etiology. Their immune profiles were compared with those of 98 patients who had no inflammatory condition, 24 who had systemic lupus erythematous, and 20 who had rheumatoid arthritis.

Patients were considered to have unique immunologic aberrations if their profile met stringent criteria: their abundance of a cell cluster had to be the highest value detected and twice as high as the next highest value measured.

Results

Unique features were not evident in any of the comparator patients but were identified in five of the 16 patients from the Undiagnosed Diseases Network:

1. A 58-year-old woman with a nine-year history of global erythroderma, anhidrosis, alopecia, and palmar plantar keratoderma—An expanded cluster of CD25^hi CD127− CD4 T cells (54% of T cells; average is 4.5%)
2. A 35-year-old woman with suspected immune-mediated cerebellar ataxia and extensive white matter disease—An expanded cluster of Vδ2 T cells (28% of T cells; average is 2.4%)
3. A 56-year-old male with a 12-year-history of progressive polyneuropathy and relapsing weakness associated with white matter disease, not characteristic of a known autoimmune neurologic disease—An expansion of CD138+ CD56+ monocytes (15% of PBMCs; average is 1.3%)
4. A 66-year-old male with a six-year history of cranial nerve palsies; a paraneoplastic syndrome was suspected, but multiple evaluations for a primary malignancy were unrevealing—An expanded, unique cluster of CD5+ Bcl-2+ B cells (22% of PBMCs; average is 0.0016%)
5. A 20-year-old woman with a one-year history of fevers, myalgias, erythema nodosum, and persistent cervical necrotizing lymphadenitis—Expanded monocyte subset that individual markers could not readily define

Patient 4

Further evaluation of patient 4 revealed chronic lymphocytic leukemia, and ibrutinib therapy was initiated. This result demonstrated the ability of broad immunoprofiling to detect a hematopoietic malignancy.

Patient 1

The striking phenotype in patient 1 prompted the researchers to investigate its potential role in her symptoms. They detected:

• Expansion of a large population of T cells that had classic features of T regulatory cells (Tregs), a cell population typically associated with immune regulation

• The expanded Treg population showed an impaired ability to suppress T cell proliferation, an expected function of Tregs

• Dense accumulation of Tregs in skin lesions from the patient

Given these findings of T-cell dysregulation, the patient was treated with abatacept, which can inhibit T-cell activation and decrease Treg numbers. That therapy reduced the number of circulating CD25^hi CD127− T cells and resulted in partial clinical response. The patient subsequently received tofacitinib, which downregulates T-cell activation and interferon, and her condition improved substantially.

These results suggest the exciting possibility that immunoprofiling can guide personalized treatment for some patients whose disease doesn’t fit into traditional diagnostic categories.