primary immunodeficiencies (wk 5)

Question 1

immunodeficiencies

Answer 1

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.

Question 2

primary vs secondary immunodeficiencies

Answer 2

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…)

Question 3

what is the most common immunodeficiency?

Answer 3

isolated IgA deficiency

Question 4

how do people with immunodeficiencies present?

Answer 4

SLIDE 6

Question 5

B cell deficiencies (primary immunodeficiencies)

Answer 5

• Isolated IgA deficiency
• Common variable immunodeficiency
• X-linked agammaglobulinemia (Bruton’s)
• Hyper IgM syndrome

Question 6

what are some primary immunodefieicnies

Answer 6

-digeorge syndromes

-severe combined immunodeficiency

-innate immunodefieicnes
–>complement deficiencies
–> hereditary hemangioma

Question 7

what is X-linked agammaglobulinemia (Bruton’s)

Answer 7

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

Question 8

X-linked agammaglobulinemia (XLA) (Bruton’s)

Answer 8

cant make pro into pre B cell

no light chain- cant make antibodies

lack tyrosine kinase

Question 9

X-linked agammaglobulinemia (Bruton’s) (XLA)

which gender?

Answer 9

males

Question 10

features of X-linked agammaglobulinemia (Bruton’s) (XLA)

Answer 10

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

Question 11

diagnosis of X-linked agammaglobulinemia (Bruton’s) (XLA)

Answer 11

B-cells are absent or very much decreased

All immunoglobulins are depressed

B-cell areas of lymphatic tissues are underdeveloped

Question 12

treat X-linked agammaglobulinemia (Bruton’s) (XLA)

Answer 12

IVIG intravenous gammaglobulin

-get antibodies from other peoples plasam= passive immunity so dont die

Question 13

common variable immunodeficiency what is the common feature in it?

Answer 13

hypogammaglobulinemia

usually involving all antibodies but sometimes only IgG

other diagnostic criteria: reduce B cells, recurrent bacterial infections

Question 14

what immunological issues can be present in common variable immunodeficiency

Answer 14

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

Question 15

similarities and difference between common variable immunodeficiency and X-linked agammaglobulinemia (Bruton’s) (XLA)

Answer 15

recurrent sinopulmonary infections, giardiasis, and serious enterovirus infections

but common variable immunodefincy
Can also have recurrent, severe herpes infections

Question 16

common variable immunodeficiency

Answer 16

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

Question 17

treatment of vcommon variable immunodeficiency

Answer 17

intravenous immunoglobulins IVIG

prognosis: survive 20 years

Question 18

isolated IgA deficiency

Answer 18

common!! esp in caucasians

Question 19

pathogenesis of isolated IgA deficiency

Answer 19

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

Question 20

symptoms of isolated IgA deficiency

Answer 20

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

Question 21

IgA deficiency and which disease to gluten

Answer 21

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

Question 22

hyper IgM syndrome

Answer 22

patient make IgM but have difficulty producing IgG, IgA, and IgE

Inability of helper T-cells to activate B-cells and macrophages

Question 23

what has a lack of function that causes hyper IgM so that they cant class switch

Answer 23

CD40L

Question 24

hyper IgM syndrome is __ linked

Answer 24

X linked; there fore males

but the other 30% of patients have other defects – inheritance pattern is autosomal recessive in these instances

Question 25

hyper IgM syndrome features

Answer 25

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

Question 26

treatment and prognosis of hyper IgM syndrome

Answer 26

IVIG and intense antibiotic prophylaxis Prognosis is guarded... meaning often not good (20% survival rate in those 25 and older)

Question 27

what is DiGeorge syndrome AKA

Answer 27

22q11 deletion

Question 28

what is the deficiency in DiGeorge syndrome

Answer 28

T cell deficiency

Question 29

what makes DiGeorge syndrome different from most other immunodeficiencies?

Answer 29

T-cell deficiency – most of the immunodeficiencies involve primarily B-cell defects (at least clinically)

Question 30

what doesnt happen in embryology/ fetal development in DiGeorge syndrome

Answer 30

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

Question 31

clinical features of DiGeoge syndrome

Answer 31

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

Question 32

DiGeorge syndrome treatment

Answer 32

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

Question 33

severe combined immunodeficiency AKA

Answer 33

BUBBLE BOY

Question 34

severe combined immunodeficiency from which pathogens?

Answer 34

recurrent, severe infections by a wide range of pathogens C. albicans, P. jiroveci, Pseudomonas, CMV, varicella, and a ton of different types of bacteria

Question 35

treatment of severe combined immunodeficiency

Answer 35

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

Question 36

what are the 2 genetic mutations that causes severe combined immunodeficnicey

Answer 36

1. x linked 2. autosomal recessive

Question 37

what is the mutation in x linked severe combined immunodeficiency

Answer 37

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

Question 38

what is the mutation in autosomal recessive for severe combined immunodeficiency

Answer 38

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

Question 39

what is the pathology of severe combined immunodeficiency?

Answer 39

small thymus with very few lymphocytes depletion of T-cell areas of other lymphatic tissues

Question 40

symptoms of severe combined immunodeficiency

Answer 40

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

Question 41

Defects in Innate Immunity --> leukocyte function --> complement system CHART ON SLIDE 23

Question 42

what is the most common compelement defect

Answer 42

C2 deficiency

Question 43

which pathways of complement is C2 in

Answer 43

lectin and classical pathway

Question 44

what does C2 complement deficiency look like

Answer 44

increased bacterial or viral infections, though many have no increased incidence of infection alternative pathway is adequate for most cases

Question 45

what can complement defects cause

Answer 45

increased risk of SLE lupus

Question 46

what are other complement deficiencies

Answer 46

properdin, factor D, C3, and ? deficiencies are uncommon, but result in more severe immunosuppression

Question 47

what type of disorder is hereditary angioedema

Answer 47

Autosomal dominant disorder

Question 48

what is the deficient in hereditary angioedema

Answer 48

deficit in C1 inhibitor

Question 49

what does hereditary angioedema result in

Answer 49

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

Question 50

which pathway for heredity angioedema is the C1 inhibitor in

Answer 50

classical pathway

Question 51

symptoms of heredity angioedema

Answer 51

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

Question 52

treatment and prognosis of heredity angioedema

Answer 52

can treat with C1 inhibitor from blood products – greatly improved prognosis mortality used to range between 20 – 30%

Question 53

use of which drug can increase risk of infections

Answer 53

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

Question 54

what infection can systemic sglucocorticoid use cause

Answer 54

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