Primary Immunodeficiencies (Pathology - Week 5) Flashcards
What is an immunodeficiency?
Any defect in the immune response that renders an individual more susceptible to infectious diseases that would be cleared by someone who was healthy
True or False: Patients with immunodeficiency are more prone to infections, which are also more likely to lead to long-term debilitation or death. They often are at higher risk of developing autoimmunity or cancer.
True
What is a primary immunodeficiency?
- mostly inborn (genetic)
- often detected in infancy or childhood (but may be detected in adulthood)
What is a secondary immunodeficiency?
Acquired due to external factors (e.g., infection, chemotherapy, medications, etc.)
When an individual has a T-cell defect, what are some examples of what they might be prone to?
- bacterial sepsis
- cytomegalovirus, EBV, varicella, chronic infections with respiratory and intestinal viruses
- Candida, Pneumocystis jiroveci
note: don’t need to memorize these, maybe just have an idea
What are special features of a T-cell defect?
Aggressive disease with opportunistic pathogens & failure to clear infections
When an individual has a B-cell defect, what are some examples of what they might be prone to?
- Streptococci, Staphylococci, Haemophilus
- Enteroviral encephalitis
- severe intestinal giardiasis
What are special features of a B-cell defect?
- recurrent sinopulmonary infections
- sepsis
- chronic meningitis
When an individual has a granulocyte defect, what might they be prone to?
- Staphylococci, Pseudomonas
- Candida, Nocardia, Aspergillus
When a person has a complement defect, what might they be prone to?
- Neisserial infections, other pyogenic (pus-forming) infections
Although primary immunodeficiences are rare, what are the most common ones?
- B cell deficiencies (e.g., isolated IgA deficiency*** - 1/600)
- DiGeorge Syndrome 1-2/2000
- Severe combined immunodeficiency 1/ 75,000
- innate immunodeficiencies (e.g., complement deficiencies 1/20,000)
True or False: Primary immunodeficiencies are common
False
Most are rare
Describe the pathophysiology of X-linked agammaglobulinemia (XLA)
- pro-B cells are unable to differentiate into pre-B cells
- can make heavy chain variable region, but not a light chain (therefore unable to make antibodies)
- lack tyrosine kinase (which initiates recombination and antibody formation)
What are the clinical features of X-linked agammaglobulinemia (XLA)?
- recurrent respiratory infections, most being gram-positive usually destroyed by IgG opsonizationa nd phagocytosis (e.g., pharyngitis, sinusitis, bronchitis, pneumonia)
- mostly only males affected (X-linked)
How is X-linked agammaglobulinemia (XLA) diagnosed?
- B-cells are absent or very much decreased
- all immunoglobulins are depressed
- B-cell areas of lymphatic tissues are undeveloped
How is X-linked agammaglobulinemia (XLA) treated?
intravenous immunoglobulin (IVIG)
What is the prognosis of X-linked agammaglobulinemia (XLA)?
- in the past, most died in childhood
- IVIG therapy now allows most people to live into their 40s (key to diagnose and treat early)
What type of immunological issues can be present with Common Variable Immunodeficiency?
- defects in most classes of antibody secretion
- inability of helper T cells to amplify antibody production
- reduced cytotoxic T cell activity
- assorted defects in the innate immune system
What is the common feature of Common Variable Immunodeficiency?
hypogammaglobulinemia (low levels of antibodies in the blood)
Note: usually involves all antibody classes but sometimes only IgG antibodies are reduced
True or False: Common Variable Immunodeficiency is not a single disease, but can occur with other defects
True
What are the clinical features of Common Variable Immunodeficiency?
- resembles XLA (recurrent sinopulmonary infections, giardiasis, and serious enterovirus infections)
- may have recurrent and severe herpes infections
- 20% rate of autonimmune disease
How do you diagnose Common Variable Immunodeficiency?
- no other B-cell abnormality detected (e.g., it’s not XLA or an isolated IgA deficiency)
- reduced immunoglobulins (but not as severely as XLA)
- B-cell areas of lymphatic tissues are usually hyperplastic
How do you treat Common Variable Immunodeficiency?
intravenous immunoglobulin (IVIG)
What is the prognosis of Common Variable Immunodeficiency?
- 20 year survival is high
- IVIG allows people to live for quite a while
How common is isolated IgA deficiency?
1/600 (the only common primary immunodeficiency)
Note: much more common in Caucasians
What is the pathogenesis of isolated IgA deficiency?
- unknown
- potentially a defect in receptor for a B-cell activating cytokine
- lymphatic tissues look relatively normal under slide
What are the clinical features of isolated IgA deficiency?
- most are asymptomatic (therefore usually not detected until adulthood)
- medical history may include recurrent otitis media, sinusitis, bronchitis, pneumonia, GI tract infections
- increased incidence of autoimmunity (lupus and RA)
- potentially deadly complication = anaphylaxis post-blood transfusion (where transfused IgA is recognized as foreign)
Why can an IgA deficiency result in a false negative in celiac positive patients testing for celiac disease?
the serology for detecting celiac disease is based on detection of IgA antibodies to enzymes that are involved in metabolizing gliadin
(so if the patient has low IgA, it probably won’t be detected)
What is the prognosis for IgA deficiency?
generally good
What do we call the condition where patients make a lot of IgM but cannot make as much IgG, IgA, and IgE?
Hyper-IgM Syndrome
What is the pathogenesis of Hyper-IgM Syndrome?
helper T-cells unable activate B-cells due to CD40 ligand deficit or lack of function
Recall: B cells can make antibodies without T cells, but it cannot undergo isotype switching without T cells
True or False: the gene for the CD40L is on the Y-chromosome, therefore affects males
False
The gene is on the X-chromosome, therefore affects males.
True or False: Hyper-IgM Syndrome is very uncommon
True (1/1,000,000 live births)
What are the clinical features of Hyper-IgM Syndrome?
- recurrent pyogenic (purulent) infections in the CNS, respiratory tract, or GI tract)
- many viral infections (e.g., hepatitis, gastroenteritis, encephalitis, pulmonary infections)
- very immunodeficient (neutrophil count decreased)
How do we diagnose Hyper-IgM syndrome?
- high IgM
- low on other antibodies
- decreased neutrophils
- decreased CD40L on T cells
How do you treat Hyper-IgM syndrome?
IVIG and intense antibiotic prophylaxis
What is the prognosis of Hyper-IgM syndrome?
often not good (20% survival rate in those 25yrs+)
What is 22q11 deletion also known as?
DiGeorge Syndrome
What is the pathogenesis of DiGeorge Syndrome (22q11 deletion)?
- T-cell deficiency
- 3rd and 4th pharyngeal pouches don’t develop, therefore short on a thymus, parathyroid glands, and some thyroid tissue
- hypothesized that T-box family of transcription factors is absent/does not function
- loss of genetic material on the long arm of chromosome 22
What is the prevalence of DiGeorge Syndrome (22q11 deletion)?
1-2/2000 (relatively common)
What are the clinical features of DiGeorge Syndrome?
- immunodeficiency, thymic hypoplasia (resulting in variable loss of T-lymphocytes)
- increased fungal and viral infections
- increased autoimmunity (RA, thyroiditis)
- cardiac abnormalities (esp associated with the great vessels)
- craniofacial abnormalities (e.g., cleft plate, high/broad facial bridge, long face, small jaw, etc.)
- developmental delay
- hypoparathyroidism (calcium and phosphorus abnormality)
- usually diagnosed in childhood (when cardiac abnormalities are identified and treated surgically)
How do you treat DiGeorge syndrome?
- avoid blood products (can result in graft vs. host disease)
- infectious disease specialist for immunotherapy, antibiotic prophylaxis
What is the prognosis for DiGeorge syndrome?
varies greatly
not everyone has every manifestation
What is Severe Combined Immunodeficiency (SCID)?
- a multitude of etiologies defined by recurrent severe infections by a wide range of pathogens (e.g., C. albicans, P. jiroveci, Pseudomonas, CMV, varicella, and many other different types of bacteria)
Note: SCID is very severe and may require bone marrow transplant or stem-cell therapies, otherwise may result in death at young age
True or False: SCID involves defects in cell-mediated (T-cell driven) immunity, but not humoral (B-cell driven) immunity
False
SCID involves defects in both cell-mediated and humoral immunity
What is the pathogenesis of SCID?
Most common mechanism: 50-60% of SCID is X-linked, due to a mutation in the gamma-chain of a variety of cytokine receptors (e.g., for IL-2, IL-4, IL-7, IL-9, IL-11, IL-15, IL-21); results in very few T cells or NK cells
Remainder 40-50% = autosomal recessive (due to mutation in adenosine deaminase or RAG mutations)
What are the pathological features of SCID?
- small thymus with very few lymphocytes
- depletion of T-cell areas of other lymphatic tissues
What are the clinical features of SCID?
- presents very early in life with recurrent severe infections
- occasionally, mother’s T cells are transferred across the placenta and cause graft vs. host disease (GVHD) where the mother’s lymphocytes attack the baby’s tissues –> manifests as morbilliform rash
What is the most common complement defect?
Side note: complement defects are innate immunodeficiencies
C2 deficiency
Why do some people with C2 deficiency have NO increased incidence of infection?
alternative pathway can be adequate for most cases
Recall: both the classical pathway and lectin pathway involve C2, and thus would be affected. However, the alternative pathway involves C3, and not C2
True or False: Individuals with C2 deficiency have an increased risk of having SLE
True
True or False: C2 deficiency is more detrimental than C3
False.
C3 deficiency is more detrimental as “all roads [complement pathways] eventually lead to C3/C3 convertase…”
and thus a deficiency would shut down all pathways and lead to more severe immunosuppression
Hereditary angioedema is a ___________ disorder and is ___________ (less/more) common than the complement deficiency disorders
autosomal dominant,
less
Hereditary angioedema involves a deficit in what?
C1 inhibitor
(note: NOT C1 protein)
Deficit in C1 inhibitor results in what?
- unchecked activation of the classical complement pathway
- increased bradykinin* production
- increased activation of certain components of the clotting cascade
Review: bradykinin elevates vascular permeability and can cause vasodilation of vessels
What are the clinical features of hereditary angioedema?
- episodic, whereby attacks usually become progressively worse
- severe abdominal pain
- vomit or diarrhea may or may not be present
- swelling of face, hands, legs, groin
- life-threatening if airways are involved
- pleural effusions (fluid in lungs) and seizures more rare
How do you treat hereditary angioedema?
C1 inhibitor from blood products (via infusion)
What is the prognosis of hereditary angioedema?
- mortality used to be 20-30%, but with C1 inhibitor treatment = greatly improved prognosis
True or False: Systemic use of glucocorticoids can increase risk of infection.
Higher doses = higher risk
2-4 weeks+ = higher risk
True
What are some infectious diseases that individuals using systemic glucocorticoids may have a higher predisposition to?
- Pneumocystis jiroveci pneumonia (a fungal infection of the lung)
- Herpes Zoster/Shingles (reactivation of varicella zoster virus = painful rash usually along a dermatome)
- Tuberculosis (conversion of latent TB to active form, affects lungs usually)
- Strongyloidiasis (a chronic parasitic infection usually acquired through direct contact with contaminated soil; may be asymptomatic and persist for decades)
How do you treat/manage Pneumocystis jiroveci pneumonia?
combination antibiotics used prophylactically and/or to treat
How do you treat/manage Herpes Zoster/Shingles?
antiviral or vaccination
How do you treat/manage Tuberculosis?
should be tested before use of glucocorticoid treatment
treated with antibiotic (isoniazid) beforehand
How do you treat/manage Strongyloidiasis?
antiparasitic
