Download Notes on Immunodeficiency

Immunology: Immunodeficiencies (Long)
PRIMARY IMMUNE DEFICIENCIES:
Frequency: ~1/10,000 births
Classification:
o T-Cell/Cell-Mediated: 10%

Hallmark: increased susceptibility to viral, fungal and protozoal infections
o B-Cell/Antibody-Mediated: 50%

Hallmark: recurrent bacterial infections (otitis media, pneumonia)
o Both B and T-Cell Immunity: 20%

Hallmark: acute and chronic infections with viral, fungal, bacterial and protozoal organisms
o Non-Specific Immunity by Phagocytic Cells and/or NK cells: 18%

Phagocytic Deficiency Hallmark: systemic infections with bacteria of usually low virulence;
infections with pyogenic bacteria; impaired pus formation and wound healing

NK Cell Deficiency Hallmark: viral infections; associated with several T cell disorders and X-linked
lymphoproliferative symptoms
o Complement Activation: 2%

Hallmark: bacterial infections; automimmunity

Note: difficult to distinguish from B-cell deficiencies clinically; look at B-cell possibilities first since
they are much more prevalent
T CELL DEFICIENCIES:

DiGeorge Syndrome: NOT INHERITED
Diseases Process:
o During 12th week of embryological development, cells do not migrate into 3rd and 4th pharyngeal pouch,
which normally give rise to:

Thymus

Thyroid

Parathyroid

Great vessels of the heart
o Heart defects are the immediate concern when the child is born; during surgery, doctors notice no thymus
is present and send for immunological consult (flow cytometry with anti-CD3 Ab to check for T cells)
o Children with DiGeorge have NO T CELLS
Facial Characteristics: fish shaped mouth; low set ears; low bridge of nose
Treatment: prognosis is bad; thankfully most patients with DiGeorge only have partial DiGeorge
o Treat symptoms
o In cases of partial, the rudimentary thymus will eventually develop some T cells (although will never reach
normal levels)

X-Linked SCID:
Disease Process: missing the γ chain of the cytokine receptor for IL-2, IL-4, IL-7, IL-9, and IL-15
o Results in a failure to activate transcription of specific genes needed for T cell function
o NO T CELLS
Treatment: need to be kept in a sterile environment right after birth (“bubble boy”) until a bone marrow transplant
can be done

Autosomal Recessive SCID:
Disease Process: missing JAK3, an intracellular signaling molecule in the same pathway described above
o Clinical presentation the same as X-linked SCID
o NO T CELLS
B AND T CELL DEFICIENCIES:

ADA Deficiency (a form of SCID): autosomal recessive
Disease Process: missing the enzyme ADA involved in DNA synthesis
o Results in buildup of toxic products, which T and B cells are particularly sensitive to
o NO B OR T CELLS
Treatment: first human disease treated with gene therapy; can also give blood transfusions ~every 30 days because
there is a large amount of ADA in RBCs that can diffuse out of the cells and protect B and T cells

PNP Deficiency (a form of SCID): autosomal recessive
Disease Process: missing the enzyme PNP; same clinical presentation as above
o NO B OR T CELLS
T+ AND B+ SCID:

Bare Lymphocyte Syndrome: autosomal recessive
Disease Process: genes for class I and II MHC present, but one or both are not expressed on the cell surface
o Missing Class I Only: no symptoms, but do have decreased CD8+ cells
o Missing Class II Only: have symptoms; cannot present Ag to T or B cells
o Missing Both Class I and II

ZAP-70 Deficiency: autosomal recessive
Disease Process: missing the ZAP-70 signaling molecule; TCR may see peptide, but cannot send signal to transcribe
genes
o Short cytoplasmic tail of TCR not able to transmit signals to the nucleus
o NO CD8+ T cells; ALL CD4+ T cells (non-functional- as shown by stimulation with PHA, CONA)
B CELL DEFICIENCIES:

X-Linked Agammaglobulinemia:
Disease Process: missing the enzyme Btk; results in all B cells being arrested in the pre-B cell stage
o NO B CELLS/Ig

IgA Deficiency: most common immunodeficiency
Disease Process: cannot class switch to IgA
o Usually undetectable (no symptoms)
o However, need to know if you lack IgA in case you need to have blood donated to you (will mount an
immune response to IgA in the donated blood since you’ve never seen it)

Hyper IgM Syndrome (X-Linked):
Disease Process: cannot class switch at all; due to lack of CD40L on T cells
o Therefore, really a deficiency with the T cell that leads to the inability to class switch for the B cell
o Only isotype made is IgM
PHAGOCYTIC CELLS:

Leukocyte Adhesion Deficiency I (LAD-I):
Disease Process: missing beta chain (CD18) of integrins found on leukocytes (cannot bind ICAM on endothelial
surface); leukocyte cannot adhere and therefore does not migrate into tissue

LAD-II:
Disease Process: missing selectin ligand on leukocyte (cannot bind E-selectin on endothelial surface); this is a weak
interaction that usually slows down the leukocyte (makes it difficult for leukocyte to adhere because it is not slowed
down)

Chediak-Higashi Syndrome:
Disease Process: issue with lysosomal enzymes, resulting in the inability to lyse bacteria once it is phagocytized

Chronic Granulomatous Disease: most common of these 4* (but still very rare)
Disease Process: inability to form oxygen free radicals; leads to bacteria living inside the cell
o Issue with b558 molecule of NADPH oxidase (X-linked)
o Issue with other molecules of NADPH oxidase (autosomal recessive; very rare)
Testing:
o NBT Test: colorless dye forms purple precipitate (formazan) when oxidize; a little outdated
o Oxidative Burst Test: colorless dye that turns green when oxidized; fluorescence measured with a flow
cytometer (more recent and applicable)
COMPLEMENT DEFICIENCY SYNDROMES:

Deficiency in EARLY Complement Components (C1,C2,C4): will have infections with encapsulated microorganisms,
since the early components allow bacteria to be phagocytized

Deficiency in MIDDLE Complement Components (C3): will have diseases similar SLE due to buildup of immune
complexes that cannot be cleared (RBCs have receptors for C3b, which normally attach to immune complexes coated
with C3b and bring them to the spleen where they are degraded; this cannot occur in the absence of C3)

Deficiency in LATE Complement Components (C5-C9; MAC): have problems with Neisseria infections

C1 Inhibitor Deficiency: results in overactivity of complement and build-up of by products; fluid build-up occurs due
to C2b accumulation; giving Epinephrine to one of these patients won’t work (need to give C1 inhibitor)