Primary Immunodeficiencies Flashcards
how do mutant genes contribute to infection?
can provide the immune evasion needed by microbes to establish infection
how do mutant genes contribute to immunodeficiency
inadequate immune responses due to these genes result in an immunodeficient state and susceptibility to colonization and infection by microbes
what are primary immunodeficiency diseases?
inherited defects in genes for components of the immune system
what are secondary immunodeficiency diseases?
not due to defective genes, but diseases that develop as a consequence of environmental factors
what environmental factors could contribute to secondary immunodeficiency diseases?
drug abuse, malnutrition, chronic disease, medication, age
what are 3 warning signs of primary immunodeficiency?
- four or more new ear infections within one year
- two or more pneumonias within one year
- persistent thrush in mouth or fungal infection on skin
what 4 clinical features are suggestive of specific types of primary immunodeficiencies?
- recurrent bacterial infections
- recurrent viral infections
- recurrent/chronic infections of soft tissues
- angioedema, autoimmunity, recurrent pyogenic and neisserial infections
what primary immunodeficiency is indicated by recurrent bacterial infections
defect in antibody mediated (humoral) immunity.
what results if there is deficiency in antibody mediated immunity?
recurrent bacterial infections involving encapsulated bacteria (strep pneumo, h influenzae, etc) or chronic enteroviral gasterenteritis and giardiasis
what primary immunodeficiency is indicated by recurrent viral infections?
defect in cell mediated immunity
what results if there is a deficiency in cell mediated immunity?
recurrent viral or mycotic infections like fungal pneumo, mucocutaneous candidiasis, PJP
what primary immunodeficiency is indicated by recurrent/chronic infections of soft tissues?
defect in phagocytic function (mostly neutrophils, maybe T cells)
what results if there is a defect in phagocytic function?
poor wound healing, soft tissue abscesses and granulomas of liver, lung, spleen, chronic gingivitis, periodontal disease, mucosal ulcerations
what primary immunodeficiency is indicated by angioedema, autoimmunity, recurrent pyogenic and neisserial infections?
defects in complement system
what causes angioedema and autoimmunity?
defects in regulatory proteins of complement
what causes recurrent pyogenic infections and autoimmunity?
defects in early components C1-4 of complement
what causes recurrent neisserial infections and autoimmunity?
defects in late components oC5-9 of complement
what causes humoral immunodeficiencies?
antibody synthesis is predominantly impaired
when do pt develop symptoms of humoral immunodeficiencies?
do not develop symptoms until over 1yo because of the disappearance of maternal IgG
symptoms of humoral immunodeficiencies?
recurrent sinopulmonary infections with encapsulated bacterial pathogens like strep pneumo and h influenzae
pathogenesis of X linked (infantile) agamaglobulinemia? (XLA)
mutation in Bruton’s tyrosine kinase (BTK), which leads to lack of synthesis or production of nonfunctional protein –> lack of B cells in the blood and tissues (and plasma cells)
what does Bruton’s tyrosine kinase do?
triggers light chain rearrangement and BCR formation from pro-B cell to pre-B cell
(B cell differentiation, maturation, BCR signaling)
what impact does BTK have on B cells?
B cell maturation arrests early in development and there is normal levels of pro-B cells in bone marrow (just don’t have pre-B, immature or mature) HOWEVER lack of B cells (and plasma cells) in blood and tissues
what impact does XLA have on Ig?
there are severe deficiencies in IgM, IgA, IgE, IgG (no plasma cells to release)
clinical presentation of XLA?
- recurrent infections in the sinuses and respiratory tract by pyogenic bacteria (strep pneumo, pseudomonas aeruginosa, h influenzae)
- otitis media, purulent conjunctivitis, bronchitis
- chronic diarrhea via giardia and enteroviruses
would immunization against H influenzae work in an XLA pt?
no because pt cannot develop their own Ab anyway
how to diagnose XLA?
- flow cytometry to determine lack of B cells in peripheral blood (no BCR, no mature B cells)
- serology to see IgG, IgA, IgM 3 standard deviations below normal (IgG may be up due to maternal IgG)
- DNA sequencing to detect BTK mutation
- PCR shows lack of BTK mRNA
- western blot shows absence of BTK protein
- history of XLA (male relative)
genetics of XLA
X linked
pathogenesis of Hyper-IgM syndrome
failure of B cells to undergo Ig class switch recombination because of X linked mutation of CD40 ligand or CD40. leads to low levels of IgG, IgA, IgE and HIGH levels of IgM
what is the consequence of CD40L or CD40 mutation?
T cells do not express CD40L upon activation. normally CD40L on TFH cells bind to CD40 on B cells which leads to centroblast proliferation and AID (activation induced cytokine deaminase) for somatic hypermutation and class switch recombination
when do symptoms for Hyper-IgM syndrome present?
during first 5 years of life
symptoms of hyper-IgM syndrome?
increased frequency of pyogenic bacteria because of neutropenia (increases predisposition for pyogenic and opportunistic pathogen)
what are hyper-IgM syndrome pt at increased risk of infection?
PJP pneumonia and chronic diarrhea/malabsorption due to cryptosporidium
how do diagnose hyper-IgM syndrome?
- flow cytometry shows numbers of B and T cells are normal to elevated
- serology shows normal to high IgM and low levels of IgG and IgA
- DNA sequencing shows CD40L mutations
pathogenesis of combined variable immunodeficiency (CVID)
B cell numbers are normal in the blood, but B cells have immature markers and their differentiation into plasma cells is defective.
mutation of CVID
- inducible costimulatory molecule (ICOS) which means no IL-21 release and no differentiation into plasma cell
- TNF receptor family transmembrane activator and calcium modulator and cyclophilin ligant interactor (TACI) - (activates IL-21 receptor signaling)
what is a secondary consequence of CVID?
1/3 pt show abnormal T cell numbers and function with a 2:1 CD8:CD4 ratio
clinical presentation of CVID?
- recurrent infections of sinuses and respiratory tract by pyogenic bacteria (s pneumo, m cattarhalis, p aeruginosa, h influenzae)
- otitis media
- chronic diarrhea (giardia)
- celiac disease
what is shown on the histology of CVID?
lymphoid tissues (LN, spleen, tonsils) may be enlarged due to reticular cell hyperplasia)
how to diagnose CVID?
- see an antibody deficiency developing at more than 2yo and poor Ig development following vaccination
- flow cytometry shows numbers of B and T cells normal to elevated
- serology shows all Ig significantly reduced, IgG and IgA 2 SD below normal (some may only show sig decrease in one isotype)
what is the most common Ab deficiency?
selective IgA deficiency (IgAD)
pathogenesis of IgAD
- B cell differentiation abnormalities
2. mucosal immunoregulatory defects
what does mucosal immunoregulatory defects cause?
proinflammatory IgG1/Th1 is produced while IgG4/Th2 and IgA are deficient
what does B cell differentiation abnormalities cause?
defect in secretion of intracytoplasmic IgA
what defect is present in 1/3 of patients with IgAD?
anti-IgA autoantibodies that bind IgA leading to its removal from the liver, high titers can lead to serum sickness and death
clinical symptoms of IgAD
most cases are asymptomatic but sinusitis and diarrhea (giardia) are common
what GI diseases are associated with IgAD?
celiac disease, pernicious anemia ( B12), ulcerative colitis, enteritis
what may be more common in pt with IgAD?
Rheumatoid Arthritis, SLE, food allergies and asthma
how to diagnose IgAD?
serology will show a pt older than 4yo with IgA of less than 10mg/dL with normal levels at 70-400mg/dL (normal IgG and IgM)
pathogenesis of transient hypogammaglobulinemia of infancy
as maternal IgG is catabolized, the infant IgG production cannot maintain adequate levels.
levels drop to >2 SD from normal age levels
what is significant about a 6mo old child?
this is the lowest point of maternal IgG serum concentration and newborn IgG production
how to treat transient hypogammaglobulinemia of infancy ?
generally no treatment is required and it fixes itself
there is no genetic component
what immunodeficiencies are humoral immunodeficiencies?
- infantile agammaglobulinemia
- Hyper IgM syndrome
- common variable immunodeficiency
- IgA deficiency
- transient hypogammaglobulinemia of infancy
what is an important cell-mediated immunodeficiency?
DiGeorge syndrome
pathogenesis of DiGeorge syndrome
abnormal migration of neural crest cells that form the 3rd and 4th pharyngeal arches during the 4th week of gestation.
what are the 3rd and 4th pharyngeal arches responsible for?
development of thymus, parathyroid gland, heart and face
genetic abnormality in DiGeorge syndrome?
microdeletion of chromosomal region 22q11.2
clinical presentation of DiGeorge
thymic hypoplasia, T cell deficiency, hypoparathyroidism, hypocalcemia, facial dysmorphism, cardiac defects
what physical deformities are found in pt with DiGeorge?
short stature, mild to moderate learning difficulties, speech and language delay, eyes slanted up or down, cleft lip and palate, small jaw and upper lip, low set ears or abnormally folding ears
what do pt with partial DGS present with?
low T cell numbers, elevated CD4:CD8 T cell ratios, low numbers of naive T cells in the blood
what do pt with complete DGS present with?
no detectable thymus or T cells, usually die because of opportunistic infections
what is a thymic shadow?
the widening of the superior mediastinal shadow by a prominent thymus seen on frontal film of infants
how to diagnose DiGeorge syndrome?
- flow cytometry/cell counts show extremely reduced CD3+ Tcells (less than 500/microL)
- CXR or MRI shows absence or extreme reduction in size of thymic image
what is required for a definitive diagnosis of DGS?
T cell deficiency/thymic absence WITH 1. cardiac defects 2. hypocalcemia or 3. deletion of 22q11.2
what are the combined humoral and cellular immunodeficiencies
- severe combined immunodeficiency (SCID)
- bare lymphocyte syndrome
- MHC class II deficiency
- ataxia-telangiectasia
- wiskott aldrich syndrome (WAS)
what 3 problems are associated with SCID?
- deficiencies in cytokine receptors
- defects impacting differentiation of progenitor cells
- deficiencies of purine salvage enzymes
what is the most common form of SCID?
lack of common gammaC chain
is X linked
what is the importance of common gammaC chain?
this chain is the signaling chain for the receptors of cytokines IL-2, IL-4, IL-7, IL-11, IL-15
what is a signaling molecule for gammaC chain receptors?
JAK-3, so may see same SCID phenotype if JAK-3 is deficient
what occurs if there is a mutation in RAG 1,2,3 genes?
these genes are involved in BCR and TCR rearrangements to if they are lacking, no B or T cells
what occurs if there is a mutation in ZAP-70?
large numbers of CD4 cells but few CD8, and neither proliferate when activated
what is omenn’s syndrome?
defect of TCR complex or CD3 that produces SCID phenotype
what genes are related to differentiation of progenitor cells?
- RAG 1,2,3
- ZAP-70
- TCR/CD3
what is adenosine deaminase (ADA)
immature T cells express high levels of ADA which breaks down adenosine and 2’ deoxyadenosine to inosine
what if ADA is deficient?
there is an accumulation adenosine and 2’deoxyadenosine in the cell
what occurs if 2’deoxyadenosine builds up in the cell?
turns into deoxyadenosine triphosphate which inhibits ribonucleotide reductase thereby impairing DNA synthesis == inability to proliferate
ALSO PROMOTES CHROMOSOME BREAKS SO WILL SEE SEVERE LYMPHOPENIA IN SCID PT
when do pt present with SCID symptoms?
initiate by 4mo
survival of SCID?
survival beyond first year is rare without aggressive therapy bc no T or B cells – stem cell therapy, exposure to pathogens eliminated (bubble boy)
clinical presentation of SCID
persistent lung infections especially PJP pneumonia, chronic diarrhea, severe mucocutaneous candidiasis, failure to thrive
histology seen for SCID
absence of all lymphoid tissue and absence thymic shadow
how to diagnose SCID
- flow cytometry shows severely low numbers of lymohocytes (immature B and T cells)
- serology shows decrease in all Ig
- absent response to skin tests and activation of mononuclear cells to mitogens
- CXR or MRI shows absent thymic shadow and all lymphoid tissue
what is the definitive diagnosis of SCID
genetic evaluation of the defect underlying SCID phenotype
gammaC, ZAP70, TCR, CD3, RAG
pathogenesis of bare lymphocyte syndrome
deficiency in MHC class I = HLA-A, HLA-B, HLA-C and beta2 microglobulin along with a loss of expression of TAP-1 and 2 or TAPbinding protein
what does TAP-1 and 2 do
transporters associated with Ag processing, required for construction of MHC class I molecules. without these molecules no Ag can enter the ER for leading onto the alpha chain or MHC class I. NO MHC I ON CELL SURFACE AND NO CD8 IF NO TAP
clinical presentation of bare lymphocyte syndrome?
persistent infections are common especially with PJP and pyogenic bacteria
how to diagnose bare lymphocyte syndrome?
- flow cytometry shows lymphopenia, poor mitogenic responses of CD8
- serology shows decrease in all IgG
definitive diagnosis of bare lymphocyte syndrome?
genetic evaluation of the defect underlying. decreased CD8, decreased all Ig means MHC I
what HLA molecules are deficient in MHC class II deficiencies?
HLA-DP
HLA-DQ
HLA-DR
pathogenesis of MHC class II deficiencies?
mutations are associated with transcription factors that promote MHC class II gene expression (CIITA, RFX)
what is seen in MHC class II deficiency?
- nearly absent CD4 cells
2. lack of differentiation of B cells into Ab producing plasma cells
how to treat MHC II deficiency?
stem cell transplant required or death occurs by 2nd decade of life
clinical presentation of MHC II deficiency?
persistent infections common esp with candida albucans, cryptosporidium parvum leading to malabsorption and failure to thrive. pulmonary infections also frequent.
diagnosis of MHC II deficiency?
- flow cytometry shows normal CD3+ T cells (inc. CD8) but extremely low CD4 T cells (nearly absent)
- serology shows extremely low all Ig
definitive diagnosis MHC II deficiency?
genetic evaluation
pathogenesis of ataxia telangiectasia
deficiency of DNA repair enzymes (ATM responsible for double strand break repair)
what does ATM mutation result in ?
enzyme deficiency results in generalized defect in tissue maturation with particular impact upon brain capillary vessels (causes dilation)
what does dilation of brain capillaries impact in ataxia telangiectasia?
involve cerebellum, causing motor difficulties (ataxia)
histology of ataxia telangiectasia
thymic hypoplasia
clinical presentation of ataxia telangiectasia in early childhood
progressive cerebellar ataxia (impaired balance and coordination) and telangiectasia that first appears as dilated conjunctival vessels (bloodshot eyes)
clinical presentation of ataxia telangiectasia in late childhood?
recurrent sinopulmonary infections initiate leading to bronchiectasis
diagnosis of ataxia telangiectasia
- flow cytometry shows a T cell deficiency (didn’t develop right)
- serology shows decrease in all Ig (double stranded break repair is important in B cell development)
pathogenesis of Wiskott Aldrich Syndrome (WAS)
loss of function mutation or lack of synthesis of WASP (wiskott aldrich syndrome protein)
X LINKED DISEASE
what does WASP do?
plays role in actin polymerization and cytoskeleton rearrangement - helps keep cells size and even distribution of shape
what occurs if WASP is deficient?
cells demonstrate abnormal size, shape and function, which is most apparent in platelets and lymphocytes
what do platelets look like in WAS?
small and aggregate, so they are destroyed in the spleen causing thrombocytopenia (WAS platelets look like specks)
what other conditions are seen in WAS and why?
severe eczema and autoimmunity because of abnormal expression of Th2 responses (cytokines)
clinical presentation of WAS?
eczema, thrombocytopenia, frequent infections, bleed and bruise easily l
what viral infections are seen most often in WAS?
HSV, VZV, molluscum contagiosum
what bacterial infections are seen most often in WAS?
pygogenic bacteria like strep pneumo, h influenzae, neisseria meningitidis
what occurs later in life in WAS patients?
more opportunistic infections develop
what autoimmune conditions are often seen in WAS patients?
autoimmune hemolytic anemia, rheumatoid arthritis
what is the most frequent cause of death in WAS patients?
hemorrhage
diagnosis of WAS?
- flow cytometry shows normal lymphocyte counts
- serology shows abnormal shaped and small platelets and thrombocytopenia, decreased IgM (other isotypes may be normal or decreased)
- ELISA shows lymphocyte function decline over time
definitive diagnosis of WAS
genetic evaluation of WASP for mutation or absence of WASP mRNA
what are the phagocyte deficiencies ?
- chronic granulomatous disease
2. Chediak-Higashi syndrome
what is the most frequent phagocyte deficiency?
chronic granulomatous disease, but it is still rare
pathogenesis of CGD
X linked form is the result of a mutation in gp1991phox (alpha chain phosphoprotein of cytochrome b558) protein
what is gp1991phox protein
alpha chain phosphoprotein of cytochrome b558 which provides electron for NADPH to convert O2 to superoxide (ROS)
what is the result of mutation of gp1991phox protein?
NADPH oxidase is not functional, so there is a failure to generate superoxide and H2O2, so intracellular killing of pathogens is defective. both neutrophils and macrophages affected
what cell type is affected in CGD?
macrophages and neutrophils
what diseases are CGD highly susceptible to?
catalase positive bacteria like staph aureus, staph epidermidis, klebsiella, salmonella, nocardia
clinical presentation of chronic granulomatous disease?
recurrent bacterial and fungal infections, frequently in lungs, LN, liver, skin and soft tissues. will present with generalized lymphadenopathy and hepatosplenomegaly.
where are infections most frequent in CGD?
lungs LN liver skin soft tissues
what are CGD infections characterized by?
formation of microabscesses and granulomas
what is commonly seen on exam in CGD?
generalized lymphadenopathy and hepatosplenomegaly
what are the results of tissue cultures in CGD?
microbes are sequestered so tissue cultures are negative but Ig are elevated
diagnosis of CGD?
- flow cytometry shows oxidative burst by neutrophils and expression of NADPH or products
- serology shows increased Ig (IgA and/or IgG and/or IgM)
pathogenesis of Chediak-Higashi syndrome
deficiency of lysosome trafficking regulator (LYST), so phagosomes do not fuse with giant secondary lysosomes
what does LYST do?
lysosome trafficking regulator is essential for assembly of cytoplasmic granules and their fusion with phagosomes to form the phagolysosome, also release of melanin from melanosomes
what is the result of deficient LYST?
phagosomes do not fuse with giant secondary lysosome, so defect leads to multiple lysosome fusion with few enzymes, and lack of melanin transport and pigmentation
what cells are affected by LYST
intracellular killing by phagocytes is slow and inefficient, and NK cell function is impaired
what do pt with Chediak-Higashi syndrome present
- oculocutaneous albinism (light colored eyes, skin, hair)
- unexplained fevers and peripheral neuropathy (seizures, weakness, gait disturbance)
- bruise easy (abn platelets)
- recurrent bacterial and viral infections leading to hepatosplenomegaly and lymphadenopathy
how to diagnose Chediak-Higashi syndrome
- see giant lysosomes in neutrophils under microscopy
2. ELISA = impaired killing by phagocytes
what molecules are impacted in early complement activation deficiencies?
lack of synthesis of C1, C2, and/or C4
infections that early complement deficiencies are susceptible to?
pyogenic bacteria
what do all complement deficiencies’ lymphoid tissues, B cell and Ig look like?
Lymphoid tissues are normal
B cell numbers are normal
Ig levels are normal to elevated
what autoimmune conditions are pt with early complement deficiencies susceptible to?
SLE (systemic lupus erythematosus)
what is the genetics of early complement activation deficiencies
autosomal dominant
what is the genetics of C3 deficiency?
autosomal recessive
what molecules are impacted in C3 deficiency?
lack of synthesis of C3
what infections are C3 deficient pt susceptible to?
pyogenic bacteria
what autoimmune conditions are pt with C3 deficiencies susceptible to?
vasculitis, glomerulonephritis
what molecules are impacted in late complement deficiencies?
lack of synthesis of C5,C6, C7, C8 and/or C9.
what infections are late complement deficiencies susceptible to ?
polysaccharide encapsulated bacteria, especially neisseria. bc these need Ab to lyse the bacteria. (MAC complex)
