HYPOGAMMAGLOBULINEMIA

OUTLINE• INTRODUCTION• DEFINITION OF HYPOGAMMAGLOBULINEMIA• METHOD OF INVESTIGATION• CAUSES OF HYPOGAMMAGLOBULINEMIA• TREATMENTS

INTRODUCTIONGamma globulins are soluble, high molecular weight globular proteins with a typical weight of about 120 kDa and above. The normal level of plasma gamma globulins is 20-30g/l and they are the only plasma proteins that do not originate from the liver.

DEFINITION OF HYPOGAMMAGLOBULINEMIA

Hypogammaglobulinemia is a pathology characterized by a decrease in the level of plasma gamma globulins that results from deficiency in B lymphocytes.

PLASMA PROTEINS INVESTIGATION

A patient with Hypogammaglobulinemia is marked by a consequent decrease in the level of gamma globulins as shown by the densitometer scanning below.

As mentioned above the main cause of this decrease is the reduction in the number of B lymphocytes produced which may arise due to different reasons.

CAUSES- Hypogammaglobulinemia may be caused by primary

(congenital) or secondary (acquired) disorders.- The primary (congenital disorders include:

A) X-linked agammaglobulinemia (XLA, Bruton agammaglobulinemia)

This is a genetic disorder that affects mainly boys. The symptoms start between the 7-9 months after a significant decline in maternal antibodies and is characterized by recurrent bacterial infections commonly H influenzae B (HIB) and S pneumoniae. This disorder has been attributed to mutation in Tyrosine kinase gene and protein.

B) Autosomal recessive agammaglobulinemia (ARA) The implicated molecules or genes include IgM heavy chain, Ig alpha, surrogate light chain, B cell linker protein (BLNK) C) Specific antibody deficiency (SAD) or specific polysaccharide antibody deficiency (SPAD) SAD is characterized by total levels of IgG, IgA, and IgM within the normal range, but with an inability to make appropriate quantities of specific antibodies and/or to retain memory of polysaccharide vaccines.

D) Hyper-IgM syndromes (including deficiencies of CD40 ligand (CD154), activation-induced cytidine deaminase [AID], and uracil-nucleoside-glycosylase [UNG]): This is a heterogeneous group of disorders in which normal or elevated IgM levels are found along with low levels of IgA, IgG, and, sometimes, IgE.

E) Common variable immunodeficiency (CVID) CVID is usually differentiated from XLA and autosomal recessive agammaglobulinemia by the presence of B-cells, visible tonsils or a history of tonsillectomy, and palpable or even enlarged lymph nodes.

F) Transient hypogammaglobulinemia of infancy

This occurs when there is a delay in the production of IgG in the baby after exhaustion of the maternal IgG around the 6th month of age. The reason for this delay is still not well understood but the child during this period remains susceptible to different kinds of infections.G) Wiskott-Aldrich syndrome This defined by mutation of WAS protein on the short arm of chromosome X and characterized by eczema, petechiae, bruising or bleeding, recurrent severe infections (including opportunistic infections) autoimmune diseases, and B-cell lymphomas.

The secondary gamma globulinemia are present in:

- Nephrotic syndrome: Decreased levels of IgG can appear with normal levels of IgA and IgM in the nephrotic syndrome.

- Protein-losing enteropathy: This occurs because of intestinal lymphatic blockade with resulting leakage of lymphatic fluid and cellular components into the lumen.

- Immunosuppressive therapy- Lymphoproliferative malignancies (leukemia &

leukocytosis B-CLL cells inhibit Ig secreting plasma proteins)

- Prematurity in infants:

TREATMENT Immunoglobulin replacement therapy is the most effective therapy against all forms of Hypogammaglobulinemia and can be achieved mainly by vaccination ( PASSIVE AND ACTIVE). Other syndromes that can not be stabilized by Vaccination e.g WAS are resolved mainly by bone marrow transplantation,

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