# Characteristics of polyclonal anti-interferon-gamma autoantibodies and novel diagnostic strategies: A prospective cohort study of new biomarkers

## TL;DR

This study identifies key features of anti-interferon-gamma autoantibodies and proposes a new diagnostic method for a rare immunodeficiency disorder.

## Contribution

The study introduces a novel diagnostic approach using affinity chromatography and absolute quantification of AIGAs.

## Key findings

- AIGA(+) patients predominantly have IgG clone types with high somatic hypermutation.
- Affinity chromatography outperforms ELISA in detecting AIGAs as an absolute quantitative biomarker.
- AIGAs exhibit strong neutralization capacity and are primarily composed of IgG3 subtypes.

## Abstract

Anti-γ interferon autoantibody (AIGA) syndrome is a widespread and grossly underestimated immunodeficiency disorder characterized by high mortality rates and a lack of standardized diagnostic methods. A highly accurate AIGA biomarker that meets the requirements of absolute quantification is urgently needed to enable the early diagnosis and treatment monitoring of the disease. In our study, we aimed to identify the primary components of AIGAs, determine their function, and develop a novel diagnostic method.

Immune repertoire sequencing and a retrospective antibody subtype index analysis were performed for typical patients. Affinity chromatography was used to isolate and purify IgGs from AIGAs in the plasma of AIGA(+) patients. The clinical application value of chromatography for testing AIGAs was evaluated in a prospective clinical cohort.

A total of 114 eligible subjects were enrolled. Immune repertoire sequencing revealed that 74 % of the AIGA(+) patients had IgG clone types, with the somatic hypermutation (SHM) analysis being the most informative. We isolated AIGAs from the blood and interpreted their affinity and major components completely. Based on the results of this prospective cohort study, AIGAs, an absolute quantitative biomarker, were significantly better than the ELISA method (Delong test, P = 0.0018).

Patients with AIGA syndrome have abnormally elevated IgG levels, with IgG3 subtypes dominating. The disorder is characterized by the rapid acquisition of polyclonal AIGAs. The obtained AIGAs had a good neutralization capacity and potential as absolute quantitative biomarkers.