2.1. PLCG2-associated antibody deficiency and immune dysregulation

At least three mutations in the PLCG2 gene have been found to cause PLCG2-associated antibody deficiency and immune dysregulation (PLAID). This condition is characterized by the development of a red, itchy rash (known as hives or urticaria) when exposed to cool temperatures, in particular cooling caused by evaporation, such as when a cool breeze blows on damp skin. Other skin rashes, recurrent infections, and autoimmune diseases, which occur when the immune system malfunctions and attacks the body's own tissues, can also occur in PLAID.

The mutations associated with PLAID are classified as germline, which means they are present in essentially all of the body's cells. They remove (delete) small pieces of DNA from the PLCG2 gene. These changes alter a region of the PLCγ2 enzyme that controls whether the enzyme is turned on (activated) or turned off (inactivated).

The altered PLCγ2 enzyme does not function normally. At low temperatures, the enzyme is constantly turned on, even when it is not needed. Signals triggered by PLCγ2 in response to cold, particularly in mast cells in the skin, likely result in hives and other skin rashes. Researchers are unsure if a similar mechanism underlies autoimmune disease in people with PLAID.

In contrast, at normal body temperature the altered enzyme's activity is reduced. The resulting impairment of B-cell and NK-cell function prevents the body from effectively fighting foreign invaders, leading to recurrent infections in people with PLAID.

2.2. Other disorders

At least two mutations in the PLCG2 gene cause a condition called autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID). The condition is characterized by episodes of abnormal inflammation throughout the body and recurrent infections. Inflammation is a normal immune system response to injury and foreign invaders. However, in APLAID the uncontrolled inflammation occurs even without infection and can damage many of the body's tissues and organs, including the skin, eyes, lungs, gastrointestinal system, and joints. Individuals with APLAID can also have reduced immune function leading to recurrent infections, similar to those in PLAID (described above). Unlike PLAID, APLAID is not associated with an allergic reaction to cold.

The PLCG2 gene mutations involved in APLAID change single protein building blocks (amino acids) in the PLCγ2 enzyme. The changes occur in the same region of the enzyme that is affected in PLAID. In APLAID, the altered enzyme is constantly turned on at normal body temperature. The overactivity abnormally increases inflammation, causing the characteristic features of APLAID. For unknown reasons, the function of B cells is impaired in people with APLAID, resulting in recurrent infections.

Several PLCG2 gene mutations have been associated with ibrutinib resistance, which is a condition in which the drug ibrutinib becomes ineffective in people with these mutations. Ibrutinib is used to treat a blood cell cancer called chronic lymphocytic leukemia (CLL). The drug normally prevents a protein called BTK from sending signals for cells to grow and divide, which blocks the growth of cancer cells. The PLCG2 gene mutations associated with ibrutinib resistance increase the activity of the PLCγ2 protein. Overactive PLCγ2 enzymes relay signals for cancerous cells to multiply despite the blockage of BTK signaling. Often two or more PLCγ2 gene mutations are found in affected individuals. Mutations in other genes can also be involved. Unlike mutations that cause APLAID and PLAID (described above), PLCG2 gene mutations associated with ibrutinib resistance arise during a person's lifetime (somatic mutations) and are present only in cancer cells.