IgG deficiency is a condition where the body does not produce adequate amounts of the most abundant type of antibody in the blood. These specialized proteins are produced by plasma cells and serve as the immune system’s long-term memory. IgG is important for combating encapsulated bacteria and neutralizing toxins, so a deficiency leaves a person vulnerable to recurrent, severe bacterial infections, especially in the respiratory and gastrointestinal tracts. Understanding the cause of the deficiency is the first step toward effective management, and these causes are fundamentally divided into inherited defects, acquired conditions, and a temporary maturational delay seen in infants.
Primary Immunodeficiencies: Inherited Causes
Primary immunodeficiencies (PIDs) are disorders rooted in genetic or congenital defects that compromise the immune system’s function. The underlying problem is typically a failure in the development, differentiation, or function of B lymphocytes, the cells responsible for maturing into antibody-secreting plasma cells.
Common Variable Immunodeficiency (CVID)
CVID is the most frequently diagnosed primary antibody deficiency, characterized by profoundly low levels of IgG, IgA, and IgM, and impaired antibody responses to vaccines. Patients have B cells that fail to undergo the final maturation step into functional plasma cells. CVID is a complex disorder diagnosed only after other known causes of hypogammaglobulinemia have been excluded.
X-linked Agammaglobulinemia (XLA)
XLA is a more severe, genetically defined defect that primarily affects males. It is caused by a mutation in the Bruton’s tyrosine kinase (BTK) gene, which arrests B-cell development in the bone marrow. This leads to a near-total absence of mature B cells and almost no circulating immunoglobulins. Individuals with XLA present in early childhood with recurrent, serious bacterial infections, while CVID can manifest at any age.
Secondary Immunodeficiencies: Acquired Causes
Secondary immunodeficiencies (SIDs) are significantly more common than primary forms. They occur when a separate disease, medical treatment, or external factor interferes with normal IgG production or accelerates its loss. Unlike the intrinsic genetic defects of PIDs, SIDs are acquired and may sometimes be reversible if the underlying cause is successfully managed. These acquired causes are broadly categorized by the mechanism of IgG reduction, which can be due to decreased production or excessive loss.
Decreased Production
Several hematologic malignancies directly impair the immune system’s ability to produce healthy antibodies. Chronic Lymphocytic Leukemia (CLL) leads to the accumulation of non-functional B cells, which crowd out the normal cells that would otherwise mature into effective plasma cells. Similarly, Multiple Myeloma (MM) involves the uncontrolled proliferation of abnormal plasma cells, which suppress the output of normal, protective IgG.
Excessive Loss
IgG deficiency can result from the body losing antibodies faster than they can be synthesized. This is commonly seen in protein-losing states, such as Nephrotic Syndrome, a kidney disorder where damaged glomeruli allow large proteins, including IgG, to leak excessively into the urine. Severe gastrointestinal disorders, often called protein-losing enteropathies, cause similar issues by allowing the antibodies to be lost through the inflamed lining of the digestive tract.
Iatrogenic Causes
A growing number of medications are recognized as causes of acquired IgG deficiency, often termed iatrogenic immunodeficiency. Certain immunosuppressive drugs used to treat autoimmune diseases or prevent transplant rejection can suppress B-cell function. A specific example is the use of monoclonal antibodies, such as rituximab, which targets the CD20 protein on B-cells, leading to their depletion and a subsequent drop in IgG levels.
Transient Hypogammaglobulinemia of Infancy
Transient Hypogammaglobulinemia of Infancy (THI) is a distinct, temporary cause of low IgG that occurs during a baby’s first few years of life. It occurs during the natural transition period from passively acquired maternal immunity to independent antibody production.
During the third trimester of pregnancy, maternal IgG antibodies are transferred across the placenta, providing the newborn with a robust initial defense against infection. These maternal antibodies gradually decline during the first six months of life as they are naturally metabolized by the infant’s body. While the infant begins to produce its own IgG antibodies shortly after birth, this production is initially slow and requires a period of maturation.
THI occurs when the drop in maternal IgG is more pronounced, and the infant’s own synthesis of IgG is delayed compared to the typical physiological timeline. The lowest point, or nadir, of IgG levels usually occurs around three to six months of age. In infants with THI, this nadir is lower than expected for their age, creating a temporary window of increased vulnerability to infection.
The condition is considered transient because the child’s immune system is expected to fully mature and normalize its IgG levels, typically resolving between 18 months and five years of age. Monitoring is key, as the resolution of the low IgG level is what confirms the diagnosis of THI and differentiates it from permanent conditions like CVID. While most children with THI remain healthy or experience only mild, recurrent infections, a small subset may require temporary supportive treatments until their immune system catches up.