genetic defect resulting in an absent spleen

• causes: genetic defect, surgical removal (splenectomy)
• symptoms: increased susceptibility to bloodstream infections to which they have no antibodies (if have antibodies then pathogens removed by liver)
• test: injection with radioactive colloidal gold; both liver and spleen will show on a scintillation counter
• why a problem: the spleen is a secondary lymphoid organ which filters the blood and removes dead/damaged cells as well as pathogens, both non-opsonized and opsonized (the spleen also makes antibodies in the white pulp), in a rapid manner

chronic local inflammations (granulomas) due to recruitment of additional cells by phagocytic cells that ingest but cannot destroy antigens due to a defect in NADPH oxidase enzyme

• causes: four different genetic defects, the most common is X-linked
• symptoms: susceptibility to bacterial and fungal infections
• test: dye cells with nitro blue tetrazolium (NBT) - healthy cells will oxidize the dye to a dark purple; cells that cannot reduce the dye do not stain
• treatment: injections of interferon-γ
• why a problem: neutrophils and other phagocytes are the main defense of the innate immune system and if they cannot destroy what they ingest and the result is granulomas which cause dissue damage in addition to the infection

leukocytes are unable to migrate from the blood to tissues due to a defect in integrins that help with adhesion and migration

• causes: genetic defect in CD18, part of the integrins LFA-1, CR3, and CR4
• symptoms: recurrent pyogenic infections, problems with wound healing, gingivitis, elevated WBC count
• test: Rebuck skin window - skin is abraded then covered and leukocyte migration over time is monitored (in this case no migration occurs) initially mostly neutrophils with monocytes appearing at 4 hours and dominant by 8; measure amount of CD18 and LFA-1 expression
• treatment: bone marrow transplant
• why a problem: severe, recurrent bacterial infections are eventually fatal

mis-/lack of regulation of inflammatory pathways resulting in intermittent inflammation without an infection

• causes: genetic mutation in genes responsible for the regulation of inflammatory pathways;  five distinct disorders
• symptoms: in the absence of infection, episodes of fever accompanied by systemic and localized inflammation in abdominal structures, joints, and skin particularly (swelling, arthritis, rash); can also lead to amyloidosis
• test: genetic testing after diagnosis based on symptoms
• treatment: IL-1 receptor antagonist (IL-1 is a pro-inflammatory cytokine that is normally controlled but isn't in these syndromes)
• why a problem: chronic inflammation damages the body

inability of innate immune system to detect pathogens

• causes: genetic mutation
• symptoms: recurrent pyogenic infections w/o fever; normal adaptive immune response but impaired antibody response to polysaccharide antigens; defect in toll-like receptor and IL-1 pathways
• test: test for TLR function, DNA sequencing
• treatment: ? only 18 patients identified so far
• why a problem: the innate immune response is an important part of the body's defense system and these receptors also play a part in triggering the adaptive immune response

failure of immunoglobulin isotype switching

• causes: defect in the gene for CD40 ligand (on X chromosome)
• symptoms: susceptibility to pyogenic and opportunistic infections; no rise in WBC count in response to infections; deficiency in neutrophils; elevated IgM level but normal IgG and low IgA levels;lack of antibody response to vaccination
• test: expose activated T-cells to soluble dyed CD40; patients' T-cells will fail to bind CD40
• treatment: gamma globulin and granulocyte-macrophage cell-stimulating factor (GM-CSF)
• why a problem: failure to isotype switch leads to the inability to produce antibodies

B-cell defect that prefents immunoglobulin isotype switching

• causes: genetic (probably autosomal recessive) mutation in gene encoding for AID
• symptoms: high IgM, low IgG and IgA; normal CD40; increased susceptibility to pyogenic infections
• test: analysis of blood lymphocytes; genetic sequencing
• treatment: ?
• why a problem: AID converts cytidine to uridine and triggers a DNA repair mechanism that causes isotype switching as well as point mutations

absence of functional T cells

• causes: several genetic defects (most common form is X-linked) in three general categories: impairment of lymphocyte survival, defect in somatic gene rearrangement machinery, defects in cytokine-mediated signals for lymphocyte maturation/proliferation
• symptoms: thymus fails to become a central lymphoid organ during fetal development; susceptible to opportunistic infections; thrush, diaper rash, persistent cough, and diarrhea; death during infancy
• test: blood test with anti-CD3 - no reaction = no T cells
• treatment: bone marrow transplant; agmma globulin therapy; gene therapy
• why a problem: without T cells you die because the adaptive immune response is nonfunctional; they are necessary not only because they kill infected cells but also because they activate B cells which for the most part cannot be activated without T cell help

cannot activate macrophages to kill intracellular microorganisms

• causes: mutation in the gene encoding IFN-γ receptor 1 chain
• symptoms: elevated serum immunoglobulin levels; enlarged lymph nodes; susceptibility to mycobacterial infection; death
• test: lymph node biopsy looking for mycobacteria; genetic mapping
• treatment: ?
• why a problem: the defects results in macrophages not being activated to change when they are infected with intracellular organisms - thus they serve as hosts in which the pathogen can replicate

a life-threatening immediate type I IgE-mediated hypersensitivity reaction

• cause: cross-linking of IgE antibodies to an allergen that induces a system-wide mast cell response (occurs upon reexposure to the allergen); often antibiotics, foods (milk, peanuts, shellfish, etc.), latex
• symptoms: very low blood pressure (due to widespread vasodilation), swelling, difficulty breathing, vomitting
• test: blood test, allergy test
• treatment: epinephrine, anti-histamines, anti-inflammatory, avoid allergen
• why a problem: without immediate treatment it can be fatal

type III hypersensitivity reaction to an antibiotic

• causes: rapid IgG response to antigen forming small immune complexes that are taken up by endothelial cells sparking inflammation (usually IV injection); often antigen is penicillin and other antibiotics as well as antitoxins to snake venom
• symptoms: hives, swelling, wheezing, fever, rash, enlarged lymph nodes and spleen, raised WBC count and plasma cells in blood
• test:blood test
• treatment: anti-inflammatory agent and anti-histamine
• why a problem: it can appear on the first encounter with the antigen and can lead to kidney failure and bleeding in the brain; the immune complexes are small enough that they lodge in tissues and cause inflammation rather than being consumed by phagocytic cells

chronic allergic disease caused by an adaptive immune response to inhaled antigen

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