10/23/17 - X-linked agammaglobulinemia

Figure 1.6 Encapsulated bacteria are efficiently engulfed by phagocytes only when they are coated with complement

-Encapsulated bacteria resist phagocytes ingestion unless recognized by Abs that fix complement. -IgG2 Abs: made against these bacteria in humans & lead to deposition of complement component C3b on bacterial surface, where it's cleaved by Factor H & Factor I to give iC3b, still bound to bacterial surface -iC3b: binds specific receptors on phagocytes (CR3 & CR4) & induces engulfment & destruction of iC3b-coated bacterium -Phagocytes also have receptors for C3b (CR1), but these are most effective when acting in concert with Fc receptors for IgG1 Abs, whereas iC3b receptor is potent enough to act alone, & is most important receptor for phagocytosis of pyogenic bacteria

Treatments for Bill's X-linked agammaglobulinemia

-began receiving weekly preps of gamma globulin rendered suitable for IV injection to keep his plasma IgG levels at 600 mg/ml -health improved, he entered med school & other than occasional bouts of conjunctivitis or sinusitis that respond to oral antibiotics, he is well. Can we explain Bill's recurrent infections & his failure to make functional B cells & antibodies? hereditary inability to make antibodies makes males susceptible to recurrent infections

patient

Bill Grignard

pedigree

Bill's younger brother suffers similar recurring bacterial infections & 2 of his uncles died in infancy from pneumonia, long before he was born.

Figure 1.1 The development of B cells proceeds through several stages marked by the rearrangement of the immunoglobulin genes

Human Ig heavy & light chain genes: found on chromosomes 14, 2 and 22; thus faulty Ig genes can't explain Bill's X-linked agammaglobulinemia .B-cell survival & differentiation depend on signaling by functional pre-B and B cell receptors.

Figure 1.2 Antibodies can participate in host defense in three main ways

LEFT: Abs bind & neutralize bacterial toxin preventing it from interacting with host cells & from causing pathology. Unbound toxin can react with receptors on host cell, whereas the toxin-Ab complex can't. Abs also neutralize complete virus particles & bacterial cells by binding to them & inactivating them. Ag-Ab complex is eventually scavenged & degraded by macrophages. Abs coating in Ag. RIGHT: consequence: without Abs you can't do a lot of things •Abs = not main system but serve as backup system •Abs can activate complement & once complement is activated you can make MAC to rupture bacteria

REVIEW •Recommendation of the script

QUESTIONS BELOW

2 strains of Streptococcus pneumoniae

R - benign & lack protective capsule and it's recognized & destroyed by host's immune system S - virulent : polysaccharide capsule prevents detection by host's immune system

Testing & results

When tested as a 2 year old, Bill's IgM, IgG & IgA serum levels found to be severely depressed

Condition - otis media

inflammation of the middle ear

3)Why was Bill treated with gammaglobulin injections, which are expensive and painful, instead of simply relying on relatively inexpensive and painless antibiotics?

it's a better long term solution; they prevent the disease from happening in the first place & restore/give the body immunity and give passive immunity from somebody else (ex: breastfeeding)

weekly gamma globulin injections

painful and expensive but the better long term solution

Treatment picked

weekly gamma globulin injections to maintain his serum IgG level & he thrived through grade school, despite recurrent bouts of pneumonia & other infections.

Problem:

•Antibiotics controlled the infections BUT as Bill grew up, he suffered repeated ear & sinus infections & twice again had pneumonia. (Pyogenic bacterial infections which tend to cause pus)

1) Why did Bill suffer recurrent pyogenic bacterial infections?

•Males like Bill with a hereditary inability to make antibodies are subject to recurrent infections •antibodies will bind to the antigen but they don't work with pyogenic bacterial infections [due to the pathogenic slime coding resisting binding] & they can't make the complement needed to coat the pathogen and fight/attack/break down the S. pyogenes

4)What evidence indicated that a mutation in Bill's germ line immunoglobulin genes was not the cause of his agammaglobulinemia?

•Since he did not have B cells/antibodies then his body did not register/recognize the pathogen at all and so the immune system can not fight what it can't see •this is not found on the X chromosome

Figure 1.5 Clinical FACS™ analysis of a normal individual (left panel) and a patient with X-linked agammaglobulinemia (XLA) (right panel) History of Problem [cont'd] -

•When Bill was 9, flow cytometry of his peripheral lymphocytes showed that 85% bound an antibody for T cell marker CD3; 55% for CD4 helper T cells and 29% CD8 cytotoxic T (normal). •But none of Bill's peripheral blood lymphocytes bound an antibody against CD19, a B-cell marker.

Condition - Erysipelas

•aka: "Ignis sacer", "holy fire" & "St. Anthony's fire" •an acute streptococcus bacterial infection of the upper dermis & superficial lymphatics

BTK gene

•encodes a cytoplasmic protein tyrosine kinase called Bruton's tyrosone kinase (Btk) •this gene is located on the X chromosome at Xq22 •defects in the gene cause failure of B cell development & agammaglobulinemia

2)What were the clinical indications that Bill has agammaglobulinemia?

•from looking at his blood lymphocytes and we saw that he shows only binding to antibodies against the T-cell marker CD3. This indicates an absence of B cells in the patient

What is the significance of the gammaglobulin injections?

•has/prepared from human plasma in it and it is IgG

Situation

•healthy for first 10 months of life then (1) developed pneumonia once (S. pneumoniae) (2) several episodes of otis media (S. pyogenes, H. influenzae, etc.) (3) erysipelas (S. pyogenes) on his right cheek over the next year

Bruton's tyrosone kinase (Btk)

•soluble/cytoplasmic protein tyrosine kinase •found in pre-B cells, B-cells & neutrophils •it's activated at different stages of B-cell development by engagement/contributing of/to both pre-B receptor & B-cell receptor [signaling, promoting B-cell survival & differentiation]

All these bacteria 1. S. pneumoniae 2. S. pyogenes, H. influenzae, etc. 3. S. pyogenes

•treated successfully with antibiotics but his mother had him constantly on antibiotics •gram positive/capsule resists a lot of the immune responses of the body •phagocytes can't eat them •resisting binding by antibodies & complement