Abstract: An increased susceptibility to bacterial and viral infections is the hallmark of explain the study rationale, primary immunodeficiencies (PID). The most common PID requiring treatment with Ig replacement (SCIg or IVIg) is Common Variable Immune Deficiency (CVID), which is diagnosed by the presence of hypogammaglobulinemia plus defective responses to vaccine antigens. Prior to diagnosis, CVID patients oftentimes develop autoimmunity that requires immunosuppression or cancers that require chemotherapy. Unfortunately, difficulties arise in making the diagnosis of CVID in adults treated with immunosuppressive drugs, steroids, or chemotherapy, preventing the timely use of Ig replacement therapies in these patients. Furthermore, CVID is difficult to diagnose in young children. Exome sequencing and other genetic methods have thus far failed to identify monogenic causes for CVID because these methods result in too many "hits" to specifically validate. At the same time, patients with derangements of signaling pathways including STAT1, STAT3, PI3K, and others have CVID, suggesting that by examining the signaling pathways, we could find consistent signs of CVID. The Investigators propose to use a broad, new screen developed by the PI to study the functional defects of human immune responses in CVID. Using time--of--flight mass cytometry (CyTOF) and phospho-specific antibodies, the investigators will simultaneously examine the major signaling pathways of all circulating innate and adaptive immune cell types at once to identify abnormal phosphorylation of signaling molecules in response to a variety of canonical stimuli. This method is innovative because it identifies signaling defects in the immune response while being insensitive to chemotherapy or immunosuppression, because the signaling responses examined are biologically upstream of immunosuppressed targets. Our approach generates a new "signaling fingerprint" for facilitating the diagnosis of CVID. Our proposal is also impactful, because knowledge gained about functional defects in CVID, when combined with whole exome sequencing, will improve the general understanding of the human immune response to infections. There are two major aims: 1) studying healthy control subjects across a variety of ages as comparisons to CVID patients, and furthermore to generate new information about how immune signaling responses change with age, which is currently unknown; and 2) studying CVID patients to identify the consistent aberrant signaling responses that will allow the acceleration of diagnosis and treatment. Design of study: The investigators propose an observational, case--control study with a single blood draw among two cohorts, patients with CVID and healthy controls. Methods: Fifty (50) CVID patients (adult and children) will be consented in Dr. Butte's Immunology Clinic at Stanford, and healthy controls (100), at the adult or pediatric primary care clinics at Stanford. There will be one blood draw of 2 mL of blood to analyzed immediately by Stanford's established phospho-CyTOF protocol in the Human Immune Monitoring Core facility at Stanford.