Immunology and Serology

CASE 1 X-linked Agammaglobulinemia

An absence of B lymphocytes.

One of the most important functions of the adaptive immune system is the production of antibodies. it is estimated that a human being can make more than one million different specific antibodies. This remarkable feat is accom­ plished through a complex genetic program carried out by B lymphocytes and their precursors in the bone marrow (Fig. 1.1). Every day about 2.5 billion (2.5 x 109) early B-ceU precursors (pro-B cells) take the first step in this genetic program and enter the body’s pool of pre- B cells. From this pool of rapidly dividing pre-B cells 30 billion daily mature into B cells, which leave the bone marrow as circulating B lymphocytes, while 55 billion fail to mature success­ fully and undergo programmed cell deqth. This process continues throughout life, although the numbers gradually decline with age.

Mature Circulating B cells proliferate on encounter with antigen and differen­ tiate into plasma cells, which secrete antibody. Antibodies, which are made by the plasma cell progeny of B cells, protect by binding to and neutralizing toxins and viruses, by preventing the adhesion of microbes to cell surfaces, and, after binding to microbial surfaces, by fixing complement and thereby enhancing phagocytosis and lysis of pathogens (Fig. 1.2).

‘Ihis case concerns a young man who has an inherited inability to make anti­ bodies. His family history reveals that he has inherited this defect in antibody synthesis as an X-linked recessive abnormality. This poses an interesting puzzle because the genes encoding the structure of the immunoglobulin polypeptide chains are encoded on autosomal chromosomes and not on the X chromosome. Further inquiry reveals that he has no B cells, so that some gene on the X chromosome is critical for the normal maturation of B lymphocytes.

This case was prepared by Raif Geha, MD, in collaboration with Ari Fried, MD.

Topics bearing on this case:

Humoral versus cell· mediated immunity

Effector functions of antibodies

Effector mechanisms of humoral immunity

Actions of complement and complement receptors

.–­ B-cell maturation

Methods for measuring T-cell function

D Case 1: X-linked Agammaglobul inemia Early pro-B cell 1lI1e pro-B cell Large pre-B cellStem cell Small pre-B cell

pre-B receptor

© l1’ It­ (5) (cW r ®a ~~ H-chain genes

L-chain genes

Su rface Ig

V-OJO-J Germline rearrangingrearranging

Germline Germline Germline

Absent Absent Absent

Fig. 1_1 The development of B c ells proceeds through several stages marked by the rearrangement of the immunoglobulin genes. The bone marrow stem cell that gives rise to the B-Iymphocyte lineage has not yet begun to rearrange its immunoglobulin genes; they are in germline configuration_ The first rearrangements of 0 gene segments to JH gene segments occur in the early pro-B cells, generating late pro-B cells. In the late pro-B cells, a VH gene segment becomes joined to the rearranged DJ H, producing a pre-B cell that is expressing both low levels of

;3 s-~-b~-~-·\

The case of Bill Grignard: a medical student with scarcely any antibodies.

Bill Grignard was well for the first 10 months of his life. In the next year he had pneu­ monia once, several episodes of otitis media (inflammation of the middle ear), and on one occasion developed erysipelas (streptococcal infection of the skin) on his right cheek. These Infections wereall treated successfully with antibiotics but it seemed to his mother, a nurse, that he was constantly on antibiotics.

His mother had two brothers who had died, 30 years prior to Bill’s birth, from pneu­ monia in their second year of life, before antibiotics were available. She also had two sisters who were well ; one had a healthy son and daughter and the other a healthy daughter.

Bill was a bright and active child who gained weight, grew, and developed normally but he continued to have repeated infections of the ears and sinuses and twice again had pneumonia. At 2 years 3 months his local pediatrician tested his serum immunoglobulins. He fou nd 80 mg dl-‘ IgG (normaI60Q-1500 mg dl-‘), no IgA (normal 50- 125 mg dl-‘), and only 10 mg dl-‘ IgM (normal 75-150 mg dl-‘ ).

Bill was started on monthly intramuscular injections of gamma globulin; his serum IgG level was maintained at 200 mg dl-1. He started school at age 5 years and per­ formed very well (he was reading at second grade level at age 5 years) despite pro­ longed absences because of recurrent pneumonia and other infections.

At 9years of age he was referred to the Children’s Hospital because of atelectasis (col­ lapse of part of a lung) and a chron ic cough. On physical ~xamination he was found to be a well-developed, alert boy. He weighed 33.5 kg and was 146 cm tall (height and

VOJ rearranged

Germline

VO,I rearranged

V-J rearranging

f.l chain transiently at surface as part of pre-B-cell receptor. Mainly intracellular

‘—–