To better understand the molecular and cellular pathways driving autoimmune diseases, we propose to deeply profile biological samples from patients with rheumatoid arthritis (RA), psoriasis (Ps), psoriatic arthritis (PsA), primary Sjögren’s syndrome (pSS) and systemic lupus erythematosus (SLE). Working closely with the AMP AIM network, we will focus on the cohorts and clinical questions defined by the network of clinicians, biologists and computational biologists together with industry and non-profit partners. For our Technology Core, we selected leading-edge multi-dimensional technologies to deeply profile end organs as well as peripheral blood from patients with autoimmunity. We assembled a team of investigators with expertise in each disease and tissue type, and who have already demonstrated the ability to develop and implement high- throughput pipelines to profile tissue and blood samples. To help us design and interpret the studies, we recruited a team of collaborators and consultants with clinical expertise in each disease, with pathology expertise in each tissue and with technical expertise in spatial profiling methods. In the first year, we will carry out the pilot phase to optimize pipelines for: i) preserving and disaggregating tissues; ii) profiling single cells using scRNA-seq/CITE-seq/TCR-BCR-seq; iii) profiling single nuclei by snRNA-seq/snATAC-seq; iv) preparing tissues for two complementary, leading-edge methods for spatial transcriptomics (Visium) and transcript imaging (MERFISH). We will iterate the protocols to optimize cell viability and yield, technical quality metrics specific to each technology and the representation of all cell types. In year 2, we will run the full set of scaled- up technology pipelines using ~50 samples per tissue type, and will assess data quality, site and batch effects and technical artifacts to inform potential modifications for the single-cell pipeline. In Years 3-5, we will profile the remaining ~1000 biopsies and ~10