primary immunodeficiencies (wk 5) Flashcards
immunodeficiencies
Any defect in the immune response that renders an individual more susceptible to infectious diseases that would be cleared by someone who was healthy
Patients with immunodeficiency diseases are more prone to contracting infections and these infections are more likely to end in long-term debilitation or death.
They also have higher risk for developing autoimmunity or cancer.
primary vs secondary immunodeficiencies
primary;; inborn, genetic
secondary;; external factors
Primary Immunodeficiencies:
Mostly inborn (genetic) and often detected in infancy or childhood
(though some are detected in adulthood)
Secondary Immunodeficiencies:
Acquired due to external factors (e.g. infection, chemotherapy, medications…)
what is the most common immunodeficiency?
isolated IgA deficiency
how do people with immunodeficiencies present?
SLIDE 6
B cell deficiencies (primary immunodeficiencies)
- Isolated IgA deficiency
- Common variable immunodeficiency
- X-linked agammaglobulinemia (Bruton’s)
- Hyper IgM syndrome
what are some primary immunodefieicnies
-digeorge syndromes
-severe combined immunodeficiency
-innate immunodefieicnes
–>complement deficiencies
–> hereditary hemangioma
what is X-linked agammaglobulinemia (Bruton’s)
primary immunodeficiency
Inability of Pro-B cells to differentiate into Pre-B cells
They can make a heavy chain variable region, but not a light chain, so they’re unable to make antibodies
Due to lack of a tyrosine kinase that initiates recombination and antibody formation
X-linked agammaglobulinemia (XLA) (Bruton’s)
cant make pro into pre B cell
no light chain- cant make antibodies
lack tyrosine kinase
X-linked agammaglobulinemia (Bruton’s) (XLA)
which gender?
males
features of X-linked agammaglobulinemia (Bruton’s) (XLA)
Recurrent respiratory infections call attention to the disease Pharyngitis, sinusitis, bronchitis, pneumonia
Most are gram positive bacteria that are usually destroyed by IgG opsonization and phagocytosis
diagnosis of X-linked agammaglobulinemia (Bruton’s) (XLA)
B-cells are absent or very much decreased
All immunoglobulins are depressed
B-cell areas of lymphatic tissues are underdeveloped
treat X-linked agammaglobulinemia (Bruton’s) (XLA)
IVIG intravenous gammaglobulin
-get antibodies from other peoples plasam= passive immunity so dont die
common variable immunodeficiency what is the common feature in it?
hypogammaglobulinemia
usually involving all antibodies but sometimes only IgG
other diagnostic criteria: reduce B cells, recurrent bacterial infections
what immunological issues can be present in common variable immunodeficiency
defects in most classes of antibody secretion,
inability of helper T-cells to amplify antibody production,
reduced cytotoxic T-cell activity, and assorted defects in the innate immune system may be present
similarities and difference between common variable immunodeficiency and X-linked agammaglobulinemia (Bruton’s) (XLA)
recurrent sinopulmonary infections, giardiasis, and serious enterovirus infections
but common variable immunodefincy
Can also have recurrent, severe herpes infections
common variable immunodeficiency
hypogammaglobulinemia
No other B-cell abnormality (isolated IgA, XLA) detected
Reduced (but not absent) immunoglobulins (not as severely reduced as XLA)
B-cell areas of lymphatic tissues are hyperplastic, usually
treatment of vcommon variable immunodeficiency
intravenous immunoglobulins IVIG
prognosis: survive 20 years
isolated IgA deficiency
common!! esp in caucasians
pathogenesis of isolated IgA deficiency
No one knows… defects in a receptor for a B-cell activating cytokine?
Reduced amounts of IgA in serum, very little in secretions, but normal levels of other antibodies and lymphocytes
Lymphatic tissues look pretty much normal under a slide
symptoms of isolated IgA deficiency
mostly asymptomatic
History significant for recurrent otitis media, sinusitis, bronchitis, pneumonia, GI tract infections
Like many other B-cell deficiency diseases – however, the immunodeficiency and subsequent infections are not nearly as severe
Also increased incidence of autoimmunity, particularly lupus and RA
A potentially deadly complication is life-threatening anaphylaxis post-blood transfusion
Recognize transfused IgA as foreign
Clinical pearl – the serology for detecting celiac disease is based on detection of IgA antibodies to enzymes that are involved in metabolizing gliadin
IgA deficiency can result in false negatives in these celiac patients
IgA deficiency and which disease to gluten
false negative in celiac!!
Clinical pearl – the serology for detecting celiac disease is based on detection of IgA antibodies to enzymes that are involved in metabolizing gliadin
IgA deficiency can result in false negatives in these celiac patients
hyper IgM syndrome
patient make IgM but have difficulty producing IgG, IgA, and IgE
Inability of helper T-cells to activate B-cells and macrophages
what has a lack of function that causes hyper IgM so that they cant class switch
CD40L
hyper IgM syndrome is __ linked
X linked; there fore males
but the other 30% of patients have other defects – inheritance pattern is autosomal recessive in these instances
hyper IgM syndrome features
Recurrent pyogenic (purulent) infections
Can be in the CNS, respiratory tract, and GI tract
Many viral infections
Hepatitis, gastroenteritis, encephalitis, pulmonary infections
These people are very immunodeficient – neutrophil counts are also decreased for unknown reasons
High IgM, low on other antibodies, decreased neutrophils, decreased CD40L on T-cells can be used to diagnose
treatment and prognosis of hyper IgM syndrome
IVIG and intense antibiotic prophylaxis
Prognosis is guarded… meaning often not good (20% survival rate in those 25 and older)
what is DiGeorge syndrome AKA
22q11 deletion
what is the deficiency in DiGeorge syndrome
T cell deficiency
what makes DiGeorge syndrome different from most other immunodeficiencies?
T-cell deficiency – most of the immunodeficiencies involve primarily B-cell defects (at least clinically)
what doesnt happen in embryology/ fetal development in DiGeorge syndrome
3rd and 4th pharyngeal pouches don’t develop…
So you’re short on a thymus, parathyroid glands, some thyroid tissue
Can also have heart and great vessel defects
Hypothesized that the T-box family of transcription factors is absent or does not function – important transcription factor for branchial/pharyngeal arch development and large vessels
Loss of genetic material on chromosome 22, on the long arm
clinical features of DiGeoge syndrome
Immunodeficiency: thymic hypoplasia results in variable loss of T-lymphocytes – low in blood and in lymphatic tissue
–>Increased fungal and viral infections
–>Increased autoimmunity (RA, thyroiditis)
Cardiac abnormalities (especially associated with the great vessels)
Craniofacial abnormalities – cleft palate, high and broad nasal bridge, long face, narrow palpebral fissures, and micrognathia
Developmental delay
Hypoparathyroidism… what electrolyte abnormality would this be associated with???
Very complex disorder, usually diagnosed in childhood when cardiac abnormalities are identified and treated surgically
DiGeorge syndrome treatment
Avoid blood products, can result in graft-vs-host disease
Infectious disease specialist for immunotherapy, antibiotic prophylaxis
Prognosis varies greatly – not everyone has every manifestation
severe combined immunodeficiency AKA
BUBBLE BOY
severe combined immunodeficiency from which pathogens?
recurrent, severe infections by a wide range of pathogens
C. albicans, P. jiroveci, Pseudomonas, CMV, varicella, and a ton of different types of bacteria
treatment of severe combined immunodeficiency
Very severe – need bone marrow transplant or stem- cell therapies or death ensues at a young age
defects in both cell-mediated and humoral immunity
what are the 2 genetic mutations that causes severe combined immunodeficnicey
- x linked
- autosomal recessive
what is the mutation in x linked severe combined immunodeficiency
mutation in the gamma-chain of a variety of cytokine receptors
signal-transducing component of the receptors for IL-2, IL-4, IL-7, IL-9, IL-11, IL-15, and IL-21
very few T-lymphocytes or NK cells… yikes
what is the mutation in autosomal recessive for severe combined immunodeficiency
due to a mutation in adenosine deaminase
–>accumulation of deoxyadenosine and its derivatives are thought to be toxic to rapidly dividing lymphocytes
RAG mutations (interferes with somatic recombination)– B- and T-cell development blocked
what is the pathology of severe combined immunodeficiency?
small thymus with very few lymphocytes
depletion of T-cell areas of other lymphatic tissues
symptoms of severe combined immunodeficiency
Presents very early in life with recurrent severe infections
Occasionally the mother’s T-cells are transferred across the placenta and cause graft-versus-host-disease (mom’s lymphocytes attack baby’s tissues), shows up as a generalized, morbilliform rash
Defects in Innate Immunity
–> leukocyte function
–> complement system
CHART ON SLIDE 23
what is the most common compelement defect
C2 deficiency
which pathways of complement is C2 in
lectin and classical pathway
what does C2 complement deficiency look like
increased bacterial or viral infections, though many have no increased incidence of infection
alternative pathway is adequate for most cases
what can complement defects cause
increased risk of SLE lupus
what are other complement deficiencies
properdin, factor D, C3, and ? deficiencies are uncommon, but result in more severe immunosuppression
what type of disorder is hereditary angioedema
Autosomal dominant disorder
what is the deficient in hereditary angioedema
deficit in C1 inhibitor
what does hereditary angioedema result in
unchecked activation of the classical complement pathway
increased bradykinin production (seems to be the most important molecule in pathogenesis)
increased activation of certain components of the clotting cascade
which pathway for heredity angioedema is the C1 inhibitor in
classical pathway
symptoms of heredity angioedema
episodic, attacks usually become progressively more severe can be precipitated by minor trauma (pressure), stress
Symptoms:
severe abdominal pain – can be mistaken for serious abdominal pathology
–.vomiting and diarrhea can also be present
swelling of face, hands, legs, groin – can be life-threatening if airway is involved
pleural effusions and seizures rarely occur
treatment and prognosis of heredity angioedema
can treat with C1 inhibitor from blood products – greatly improved prognosis
mortality used to range between 20 – 30%
use of which drug can increase risk of infections
systemic glucocorticoid use
Increased risk with higher doses (e.g. 15-30g prednisone) and for greater than 2-4 weeks
E.g. in IBD patients on corticosteroids alone,
the relative risk of bacterial infections was found to be 5-fold higher
4-fold higher for other infections like strongyloidiasis and tuberculosis
1.5 fold higher for viral infections
what infection can systemic sglucocorticoid use cause
herpes zoster (shingles)
tuberculosis
strongyloidiasis
Pneumocystis jiroveci pneumonia
=——–
Pneumocystis jiroveci pneumonia
Fungal infection of the lung
Combination antibiotics prophylactically or treatment
Herpes Zoster (Shingles)
Reactivation of varicella zoster virusàpainful rash Vaccinations or antiviral
Tuberculosis
Conversion of latent TB to active formàusually affects lungs
Should be tested for before glucocorticoid treatment and treated with
Strongyloidiasis
A chronic parasitic infection, usually acquired through direct contact with contaminated soil (can be asymptomatic)
Can persist for several decades and can reactivate with glucocorticoid exposure. Treated with antiparasitic
Other opportunistic infections?
Aspergillosis, nontuberculous mycobacterial disease, candidiasis, and cryptococcosis
Evidence for these is less robust
