BIOL 3500: Case study (T cell: B cell interaction) 3/9
What does CD40/CD40L interaction look like in B cell help?
1. B cell binds virus thru viral coat protein. Virus particle is internalized and degraded 2. Peptides from internal proteins of the virus are presented to the T cell, which activates the B cell 3. Activated B cell produces antibody against viral coat protein
How do we treat Dennis's XHIM?
1. Regular infusions of IgG 2. Prophylactic treatment for Pneumocystis Carinii pneumonia 3. Patients with persistent neutropenia may also respond to granulocyte colony stimulating factor (G-CSF) therapy 4. Bone marrow transplantation or cord blood stem cell transplantation has been advocated in recent years
What happens to males with a defect in the CD40L gene?
1. isotype switching fails to occur 2. The initial activation and expansion of T cells in response to protein antigens is greatly reduced 3. the activation of macrophages is reduced 4. Neutropenia (deficient in neutrophils)
What symptoms was Dennis Fawcett showing and how was he initially treated?
5 y.o that has had severe acute infection of the ehmoid sinuses (ethmoiditis) Has had recurrent sinus infection since he was 1 y.o. Had pneumonia from an infection from Pneumocystis carinii when he was 3 y.o. successfully treated infections with antibiotics
Why is isotype switching important?
Because IgM really only activates complement system, need isotype switching for functions such as neutralization, opsonization, transport across epithelium and placenta, etc
In the most common form of HIM there is a defect in the gene that encodes for ___________
CD40 ligand, a protein on T cells which binds to CD40 on B and other immune cells (macrophages, DCs, mast cells)
Dennis's B cells expressed IgD as well as IgM on their surface. Why was he able to isotype switch from IgM to IgD?
Co-expression of IgM and IgD does not require isotype switching, just differential mRNA splicing
Deficiency in any of the following would induce a hyper-IgM syndrome except: A) AID B) CD40L C) CD40 D) MHC class II E) TdT
E) TdT
What is Hyper IgM Immunodeficiency (HIM) and what is an individual with HIM suceptible to?
HIM is a rare primary immunodeficiency characterized by the production of normal to increased amounts of IgM antibody and an inability to produce sufficient quantities of IgG, IgA, and IgE Individuals with HIM are susceptible to recurrent bacterial infections
What was weird about Dennis's blood test since he had a severe bacterial infection (streptococcus) ?
His WBC count was low with a low count of neutrophils, normal lymphocyte numbers, and a high amount of monocytes
What is XHIM and what are some facts about it?
It is HIM that is inherited as an X-linked recessive trait, and is usually found only in boys can have cases of XHIM that are 'new mutations' where there is no family history of the disease
What was found when Dennis was tested for antibodies to streptolysin O (antigen secreted by Streptococci) and tested for immunoglobins
No antibodies! He also was unable to make antibodies to the DPT vaccine When tested for immunoglobins, the IgG level was low, IgA was undetectable, but IgM was high (in his B cells was found to product both IgM and IgD on cell surface but none with IgG or IgA) It was also found that in the lymph node there was poorly organized structures with an absence of secondary follicles and germinal centers His activated T cells did not express CD40L
Why could Dennis make antibody responses against A and B blood antigens?
because the antibody response was of the IgM class only
Why did Dennis make antibodies to blood group A and B antigens, but not to the DPT antigens?
blood group A and B antigens are T-independent, while DPT is T-dependent
Why would XHIM males become profoundly deficient in neutrophils? (very prominent feature of the disease)
the interaction of the CD40L with CD40 on macrophages is required for the secretion of GM-CSF by macrophages ---> GM-CSF is crucial for mobilizing neutrophils from bone marrow