Hyper IgM immunodeficiency

Elements of the case

• male patient with recurrent bacterial infections; other infections start at about one year of age, leading to failure to thrive

• positive family history. in practice, think who you need to ask what to elicit relevant family history

• normal number and distribution of white cells

• normal numbers of B and T cells in the blood

• high levels of IgM and very low levels of IgG and A (also low levels of IgE)

  • these people never have an allergy, but the disease is probably too high a price to pay for this luxury

  • normal to high RBC isoagglutinins

• since this disease is ultimately caused by failure to class switch and characterized by recurrent bacterial infections, we know that class switching is important for combating bacterial infections

• lymph nodes do not make germinal centers. ordinarily, this is where B and T cell cooperation takes place

• T cells do not bind soluble CD40, indicating that patients have no CD40L on their T cells. this is the molecular defect in this disorder

Principles to understand

• CD4+ T cells help B cells make antibody

• CD40:CD40L help with in T-cell help of B cells and in T-cell stimulation of APC

• CD40:CD40L interaction is necessary for class switching from IgM to IgG, A, E

• T-cell-dependent and -independent antigens

  • polysaccharides—large molecules with many repeating subunits—can cause a B cell to bind. these are generally T-cell independent antigens

  • proteins, such as those derived from ingested pathogens, are generally T-cell dependent antigens

• T-cell activation of macrophages of macrophages through CD40:CD40L

• Dr. Baird’s anecdote about waking up in lecture: sometimes when you wake up, you jerk. he was sitting in the front row of the lecture hall in college and he fell asleep and woke up with a start. the jerk was so forceful that he flung his pencil forward, narrowly missing the lecturer’s right ear. the lecturer didn’t notice

Immunoglobulin specialization of functions and distribution

• don’t need to memorize the whole table

• note, however, that some IgG subclasses are very good at opsonization or help NK cells

• some IgG activates complement system, but IgM is good at it too

The genetics of isotype switching

• IL-4, IL-6, IL-2, CD40:CD40L interaction all contribute to isotype switching. however, CD40:CD40L interaction is necessary

• ultimately, sequences of DNA are looped out and this creates different isotypes of immunoglobulins

B cells

• B cells bind virus through viral coat protein; virus particle is internalized and degraded

• one or more chewed-up particles attaches to MHC class II molecules and the MHC is transferred to surface

• T_H2 cells recognizes MHC. CD40 on B cell binds to CD40L on T cell. T cell secretes cytokines and the B cell is induced to class switch

• understand that B cells are antigen-presenting cells, but they are not good APCs for initial presentation to activate a T cell. activation of T cells requires B7 interacting with CD28 (i.e., interaction of CD28 with CD80 and CD86)

lymph node biopsy is telling but not necessary to make this diagnosis

Category: Pathology Notes