CTLA-4 Deficiency

Clinical manifestations of CTLA-4 deficiency

Germline mutations in the CTLA4 gene are a risk factor for the development of an immune dysregulation- and immunodeficiency syndrome with autoimmunity and, in most cases, to hypogammaglobulinemia. In about two thirds of the patients, the immunological phenotype shows typical changes of a primary antibody deficiency. First symptoms often include recurrent respiratory infections such as pneumonia, bronchitis and sinusitis, and wasting enteropathy that can lead to weight loss and potassium loss. Several patients first presented with autoimmune diseases such as cytopenia or autoimmune thyroiditis. Hypogammaglobulinemia often manifests at a later stage. In patients examined at the CCI, the age of onset was between 7 and 41 years. Respiratory tract infections, mostly due to viral or bacterial pathogens like Haemophilus influenzae and Streptococcus Pneumonia, may start during early childhood and remain a recurrent problem also in adults. Opportunistic infections such as tuberculosis and aspergillosis are also seen. As the infections can be rather severe and can lead to end-organ damage, they should be treated rapidly and aggressively.

Many patients present either with granulomatous infiltrations such as into the brain or with extensive CD4+ T cell infiltrations into various organs like the intestine, kidneys, bone marrow and brain. Theses infiltrations can lead to a progressive loss of organ function and, depending on the organ, to secondary complications like nephritis or neurological symptoms. About two thirds of patients suffer from granulomatous-lymphocytic interstitial lung disease (GLILD) that can lead to lung fibrosis.  Additionally splenomegaly and lymphadenopathy may develop. CTLA-4 deficiency also increases the risk of developing autoimmune diseases, such as Immune Thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA) or autoimmune thyroiditis.

Immunological phenotype

Peripheral blood shows typical changes of a primary antibody deficiency, as it is often seen in patients with CVID (Common Variable Immunodeficiency). About half of the patients that have been diagnosed at the CCI with CTLA-4 deficiency were previously diagnosed with CVID. In almost all of the patients the levels of at least one of the immunoglobulin subclasses are reduced. In addition, lymphopenia, reduced B- and NK- cells, reduced gamma delta T-cells, reduced switched memory B-cells and a shift from CD45RA+ naïve to CD45RO+ memory T-cells are often seen. The CD4/CD8 ratio is often normal; CD19+ B-cells often decline over time.

Diagnosis

The clinical and immunological phenotype can be quite variable, which makes a conclusive diagnosis difficult. This is why a firm diagnosis for CTLA-4 deficiency must be done by a genetic test in specialized laboratories. The family history can be helpful for finding the diagnosis. The inheritance of CTL44 deficiency follows an autosomal dominant pattern; the chance of inheriting the mutation is 50%.

Therapy

In cooperation with the NIH in Bethesda, USA the CCI has established a therapy stepwise protocol that is guided by the clinical manifestations of the individual patient. It includes an antibiotic prophylaxis and an immunoglobulin substitution. In patients with lymphocytic organ infiltrations a combined therapy of immunosuppressive medication with drugs like Prednisone, Rapamycin, and Rituximab has been successful. In selected patients Abatacept, which functions similar to the body’s one CTLA-4 protein has shown promising results. If you are interested in further details of our protocol you are very welcome to contact us.