Rita Douda

Immunodeficiency Lecture in Bullet Point Format

Primary Immunodeficiency (ID)

B cell
o XLA (Burtons Agammaglobulinemia)
Failure of B cell maturation
Inadequate Ab
Inc. infection
Btk Gene Mutation, X linked.
No Mature B cells No Plasma cells
Few or no Ig isotypes
T cells are normal
Cell-mediated response is normal
Secondary lymph organs do not have germinal centers. Germinal follicles
are small or absent.
Symptoms begin 1st year. Some remain asymptomatic until teens. Ave
age of Diagnosis is 2.5 years
Present w recurrent respiratory infections, pharyngitis, otitis media, GI
viruses. Persistent infection with Giardia.
Treatment: Bone marrow transplant, hematopoietic stem cell transplant
(HSCT), antibiotic therapy (aggressive, prophylactic), avoidance of live
vaccine.
o Selective IgA Deficiency (Hypogammaglobinemia)
More common (1/100-1/1000)
Genetic defect = outside Ig Complex
IgA deficiency is due to inability of IgA B-cells to become plasma cells. .
Normal IgG and IgM
Onset childhood or teens.
Many people are asymptomatic. Some have GU and respiratory
infections due to decreased IgA on mucosa.
Predisposed to malabsorption and allergies/autoimmune.
Treat with antibiotics.
Avoid IgA blood products to avoid anaphylaxis.
No treatment to cure. Diagnosis is to prevent life threatening blood
transfusions.
o Common variable immunodeficiency (CVID)
Low IgG and IgA (sometimes low IgM)
Mutation in B cell maturation OR Ig alpha chain.
Impaired Ab response to infection and vaccines
No plasma cells but yes Mature B cells
Block Ag-stimulated B cell differentiation
Deficiency in T helper cells
Appears either early or late 1-5 years or 16-20 years. Diagnosis of
exclusion
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Variable presentation depending on the person. Upper/lower respiratory

and GI infections, severe pyogenic pneumonia, diarrhea (Giardia), herpes
Simplex virus, autoimmune disorders, lymphoid tumors (300x increase
lymphoma), malabsorption via lymphoid hypoplasia.
Treat with HSCT, lifelong IV Ig replacement therapy, antibiotics to prevent
infections, keep fluid levels and nutrition good.
T cell
o Hyper IgM Syndrome (HIGMS)
Defective isotype switching which results in normal or high IgM and NO
IgA,E,G
Problem with B and T cell interaction
4 genetic defects 2 phenotypes
CD40L (T cells) defect, CD40(B cells) defect impair interaction
between CD40L/CD40
AID Defect, UNG Defect interfere with class switching
recombination events
CD40/CD40L mutation phenotype
No help from T cells
no B cell heavy chain isotype switching
no memory B cells or GCs during humoral response.
Myelocyte promyelocyte differentiation block
Defective GCs in lymphoid organs. No GC in lymph nodes
B cells are intrinsically normal. B cell response to T cell
INDEPENDENT Ags is normal.
Opportunistic and pyogenic infections recurrent
Neutropenia
Risk of lymphoma
Abs against neutrophils and platelets and RBCs
Chronic parvovirus, anemia
Low IgG, IgE and IgA
Liver failure, malignancy.
AID/UNG mutation phenotype
Internal B cell defect
Prevent B cell development
Hyperplasia Lymph Nodes
Hypertrophy tonsils
Symptoms in infancy.
Recurrent URT and LRT infections. Predisposed to pneumocystis
pneumonia.
Prominent germinal centers
Recurrent infections are NOT opportunistic.
Treatment = HSC transplant, IV Igs, gamma globulin infusions. Antibiotics
to control and reduce infection as well as prophylactic.
o MHC-II Deficiency (Bare Lc Syndrome, BLS)
A type of SCID
Hallmark = no MHC-II increased extracellular infections.
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Defective responses to Ag cell mediated and humoral

Normal MHC II CD4, T cell mediated response, regulate Ab
production, tolerance
Genetic defect is AR. Gene regulation disease, defect is in the regulatory
region outside of the MHC Locus.
No humoral or T cell mediated response
Lymphocytes have decreased ability to stimulate HLA
Panhypoglobulinemia (almost agammaglobulinemic)
Less CD4 T cells, More CD8 T cells
Normal B cells, Normal LEVELS of T cells
4 months diagnosis age. Present with symptoms early
presentation recurrent infections pseudomonas, salmonella, e coli, strep
and staph. Lymphomas, Autoimmune, failure to thrive, rapid progression.
Life span 6 months to 5 years.
Treatment HSCT/bone marrow transplant, IV Igs, Antibiotics to treat
and prevent infections, avoidance of live vaccines and non-irradiated
blood products including platelets.
o Wiskott-Aldrich Syndrome (WAS)
Defect in WASP protein which is a transmembrane protein to
cytoskeleton. Normal functions cell motility, T cell APC synapse,
Macrophage organization
X-linked
Clinical triad petechia due to thrombocytopenia, eczema, pneumonia,
B cell lymphoma/other cancers
Affects B and T cells. Lymphocytes can be normal in infancy.
Develop lymphopenia as they grow up by age 6
Normal IgG, Low IgM, High IgE and IgA
Gradually lose thymic lymph node and splenic tissue.
Decrease in delayed hypersensitivity
Diagnose average age 2 years old.
Develop eczema by 1 year.
Lifespan 8 years
Iron deficiency
Recurrent infections, gradual loss of both humoral and cell mediated
immune response.
Die of fatal infections when young OR lymphoid malignant in
adolescence.
Few platelets (thrombocytopenia fatal bleeding)
Treatment HSCT can cure!
IV Ig, avoid live vaccines, avoid blood products non-irradiated,
need transfusions, antibiotics, steroids to control eczema,
surveillance for cancers.
Acronym: WAITER: Wiskott Aldrich Immunodef. Thrombocytopenia,
eczema, recurrent infection
B/T Severe Combined ID (SCID)
o X Linked recessive (SCID)
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Very small thymus. No thymic shadow. No Hassalls corpuscles, few or

no Lymphocytes.
Abnormal dendritic cells and epithelial cells. Hypoplastic secondary lymph
organs.
Genetic defect is a mutation in the gamma chain subunit of cytokine
receptor. This codes for IL2, 7,15.
Low T cells, no T cell mediated immunity, no mature T cells. B cells are
present but not functional. Ab synthesis is impaired
No tonsils
Diagnose about 6 months
Infections that persist despite treatment. Dont respond to treatment.
Oral thrush and candida diaper rash.
Failure to thrive
Sepsis pneumonia
Fatal outcome within 1st year due to terminal infections unless bone
marrow transplant is given.
Treatment avoid live vaccine, regular intravenous Ig treatment before
there is too much deterioration, antibiotics to prevent infection
o ADA Deficiency
Defective nucleotide salvage pathway
Adenosine deaminase
Ubiquitous housekeeping enzyme in purine metabolism
Catalyzes deamination of adenosine released from dying cells after
infection.
accumulate lymphotoxic metabolites. Metabolic poisoning of developing T
cells.
Small thymus
Depletion of T or B cell zones.
Hypoplastic secondary lymphoid tissue
Early onset group 3 months. Lymphopenia, no cellular or humoral
immunity, failure to thrive, rapidly fatal infections.
Late onset group: 2-15 years. Less severe immunodeficiency
Treatment HSCT, bone marrow, IV Ig, ERT (modified form of the
enzyme), avoid live vaccine, avoid adenine based antiviral agents
because they are substrates for ADA.
o RAG deficiency (Omenn Syndrome - OS)
Defect in VDJ recombination.
Defect is in RAG 1 or RAG 2. Failure of any part of VDJ recombination
leads to SCID.
Thymic dysplasia, low Abs, undetectable cervical LN and tonsils
Gradual onset, 2-3 months. Opportunistic infections.
Scaly erythematous rash severe dermatitis.
Lymphadenopathy, failure to thrive
Recurrent pneumonia
Therapy resistant muco-cutaneous candidiasis.
Chronic bacterial infections, otitis, purulent rhinitis, conjunctivitis,
meningitis, local abscesses.
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Intracellular parasites/viruses lethal

Omenn syndrome can be from RAG, ARTEMIS defects.
Infants present with massive inflammatory infiltrates in skin, gut,
liver, spleen, hepatomegaly, splenomegaly, anemia, eosinophilia,
recurrent infections. Survival dependent on reconstitution of
immune system
Erythroderma
o DiGeorge Syndrome (DS)
Can be classified as a pure T cell defect. Defective thymus
Abnormal migration of neural crest cells
90% have 22q deletion
Incomplete DS thymic, parathyroid hypoplasia. May improve with age.
Complete DS thymic aplasia, no T cells in the lymph nodes, spleen or
blood. Defective T cell immunity.
Neonatal period hypocalcemia can cause tetany and seizures
Parathyroid glands are responsible for increasing calcium
Impaired t cell production but may improve
Heart defects, hypocalcemia
Cleft palate common, dysmorphic faces, wide eyes slant down, low ears,
hyper-nasal speech.
Novel Primary immunodeficiency
o Decrease in the ability to overcome a single or narrow range of infections. More
common and less severe.
Secondary ID: HIV/AIDS. Initial infection affects immunocompetent individual. Triggers immune
response accompanied by non-specific, self-limiting symptoms. 2-4 weeks, many get severe flu
like symptoms.

HIV
o Stage 1: Acute primary infection
Initial response to infection in immunocompetent person
o Stage 2: Asymptomatic Stage
Prolonged phase
Increased viral replication, decreased immune system. Gradual decline in
CD4 T cells.
o Stage 3: Symptomatic Stage
Fever, rash, fatigue
Massive viremia, breakdown host defenses
Preset with fever for more than 1 month
Weight loss
Fatigue
Less than 500 CD4 T cells/microliter.
AIDS
o Stage 4: AIDS/Final/Crisis Stage
Any HIV infected person with CD4 of 200 or less per microliter.
Usually accompanied by opportunistic infections
Muscle wasting, neoplasms, viremia.