How CHAI Affects Your Body: Multi-System Symptoms

One of the most defining characteristics of CTLA4 haploinsufficiency (CHAI) is its “multi-system” nature. Because the CTLA-4 protein regulates the immune system, dysregulation allows immune cells to move into and affect almost any part of the body ^[1].

It is important to remember that no two people with CHAI are exactly alike. You may experience several of these symptoms, or perhaps only one. Symptoms can also change or evolve over many years ^[2]. Furthermore, the symptoms described below can also be caused by unrelated infections or medication side effects, so they require evaluation rather than assumption.

Blood and the Immune System

The most common symptoms of CHAI involve the blood and the immune system itself. Doctors often see a situation where the immune system is both overactive and failing to protect the body.

• Autoimmune Cytopenias (62% in one cohort): This occurs when the immune system mistakenly attacks and destroys blood cells ^[1]. Common forms include Immune Thrombocytopenia (ITP) (low platelets, leading to easy bruising or bleeding) and Autoimmune Hemolytic Anemia (AIHA) (low red blood cells, causing fatigue and paleness) ^[3][4]. When both occur together, it is known as Evans Syndrome ^[4].
• Hypogammaglobulinemia (84% in one cohort): This is a technical term for low levels of protective antibodies (immunoglobulins) ^[1]. This leaves you more vulnerable to recurrent infections, such as pneumonia or ear infections ^[5].
• Lymphoproliferation (73% in one cohort): This is the term for an accumulation of immune cells that causes parts of the lymphatic system to swell ^[1]. This commonly shows up as swollen lymph nodes (lymphadenopathy), an enlarged spleen (splenomegaly), or an enlarged liver (hepatomegaly) ^[6][7].

Lung and Respiratory Involvement

Respiratory symptoms are reported in approximately 68% of affected individuals in some studies ^[1]. The immune system can cause inflammation in the lung tissue that isn’t caused by an infection. On a CT scan, doctors may look for nonspecific imaging findings that require specialist interpretation ^[8][9]:

• Pulmonary Nodules: Spots that can reflect inflammation, but could also be infection.
• Ground-Glass Opacities: Hazy areas that look like “fog” on the scan, which can reflect infection, inflammation, or hemorrhage.
• Bronchiectasis: Damage and scarring of the airways, often from repeated infections.
• GLILD: A specific type of lung disease (Granulomatous-Lymphocytic Interstitial Lung Disease) where granulomatous and lymphocytic inflammation invades the lung tissue ^[9].

Digestive System and Nutrition

Gastrointestinal (GI) issues affect about 59% of patients in some cohorts ^[1]. This is often called immune-mediated enteropathy. The immune system attacks the lining of the gut, which can lead to ^[10][11]:

• Chronic Diarrhea: Severe, ongoing diarrhea that requires careful management.
• Malabsorption: The body’s inability to take in nutrients from food.
• Nutritional Deficiencies: In severe cases, significant unintentional weight loss and marked wasting can occur due to the body’s high-inflammatory state and poor nutrient absorption ^[12].

Neurological and Brain Involvement

Neurological symptoms occur in roughly 29% of cases ^[1]. These can be some of the most complex symptoms to manage because, in one specific study, MRI lesions were sometimes clinically silent—meaning they showed up on an MRI before symptoms were felt ^[13]. Manifestations can include:

• Inflammatory Lesions: Areas of inflammation in the brain or spinal cord that can mimic other diseases like multiple sclerosis ^[13][14].
• Headaches and Seizures: Resulting from inflammation or changes in the central nervous system ^[13][15].
• Vision or Coordination Changes: Occasionally, patients may experience balance issues (ataxia) or changes in their sight ^[13].

Because CHAI can affect so many areas, your care will likely involve a team of specialists—including immunologists, hematologists, and gastroenterologists—who work together to monitor these different systems ^[16].