Diseases Flashcards
X-linked agammaglobulinemia
B-cell disorder
Defect in BTK -> no B cell maturation…stops maturing at the Pre-B cell stage because BTK functions to help make the BCR
X-linked recessive
presentation: recurrent bacterial and enteroviral infections after 6 months
findings: absent B cells in peripheral blood; decrease Ig of all classes; absent/small lymph nodes and tonsils
treatment: IVIG, antibiotics
Selective IgA deficiency
B-cell disorder
most common primary immunodeficiency
presentation: majority Asymptomatic. can see Airway and GI infections, Autoimmune disease, Atopy, Anaphylaxis to IgA containing products
findings: low IgA levels with normal IgG and IgM
treatment: IVIG, antibiotic, do not give blood products
Common variable immunodeficiency
B-cell disorder
many causes but lead to a defect in B cell differentiation
Presentation: age ~20-30s, increase risk of autoimmune disease, bronchiectasis, lymphoma, sinopulmonary infections
findings: decreased plasma cells and Igs
treatment: IVIG
DiGeorge syndrome
T-cell disorder
Deletion: 22q11.2; failure to develop 3rd and 4th pharyngeal pouches leads to absent thymus and parathyroids
presentation: tetany (hypocalcemia), recurrent viral/fungal infections (T cell-deficiency), conotruncal abnormalities
findings: low T cells, low PTH, low Ca+2, absent thymic shadow on CXR
treatment: thymus transplant in leg, HSCT
IL-12 receptor deficiency
T cell disorder
low TH1 response; autosomal recessive
presentation: disseminated mycobacterial and fungal infections; may present after administration of BCG vaccine
findings: decreased IFN-gamma
Hyper IgE syndrome
T cell disorder
also called Job syndrome
mutation in STAT3 leads to deficiency of TH17 cells which leads to impaired recruitment of neutrophils to sites of infection; autosomal dominant
presentation: FATED: coarse Facies, cold (noninflamed) staphylococcal Abscesses, retained primary Teeth, increased IgE, Dermatologic problems (eczema)
findings: increased IgE and decreased IFN-gamma
Chronic mucocutaneous candidasis
T-cell disorder
many causes
presentation: noninvasive candida albicans infections of skin and mucous membranes
findings: absent in vitro T cell proliferation in response to Candida antigens; absent cutaneous reaction to Candida antigens
Severe combined immunodeficiency (SCID)
T and B cell disorder
X-linked: mutation in IL-2R gamma chain (T-B+NK-)
somatic: mutation in ADA (toxic accumulation of adenosines in lymphocytes; T-B-NK-), PNP (toxic accumulation of inosines in lymphocytes; T-B-NK-), JAK3 (signaling pathway on gamma chain for lymphocytes; T-B+NK-), RAG1/2 (no TCR/BCR receptors; T-B-NK+)
presentation: failure to thrive, chronic diarrhea, thrush, recurrent viral, bacterial, funagal and protozoal infections
treatment: bone marrow transplant asap
findings: low T cell-receptor excision circles (TRECs), absence of thymic shadow, germinal centers and T cells
Ataxia-telangiectasia
B and T cell disorder
defects in ATM gene -> failure to repair DNA DSB -> cell cycle arrest
presentation: triad: cerebellar defects (Ataxia), spider Angiomas (telangiectasia), IgA deficiency
findings: increased AFP, decreased IgA, IgG and IgE, lymphopenia, cerebellar atrophy
treatment: IVIG
Hyper IgM syndrome
B and T cell disorder
most commonly due to defective CD40L on Th cells -> class switching defect; X-linked recessive
can also be autosomal: mutation in activation-induced deaminase (AID), which is important in germical center antibody class switching; no somatic hypermutation
presentation: severe pyogenic infections early in life; opportunisic infection with Pneumocystis Cryptosporidium, CMV
findings: normal or increased IgM, very low levels of IgG, IgA, and IgE
treatment: IVIG
Wiskott-Aldrich syndrome
B and T cell disorder
mutation in WAS gene: T cells unable to reorganize actin cytoskeleton; x-linked recessive
presentation: WATER: Wiskott-Aldrich = Thrombocytopenia, Eczema, Recurrent infections; increased risk of autoimmune disease and malignancy
findings: low to normal IgG, IgM; increased IgE and IgA; fewer and smaller platelets
treatment: IVIG, antibiotics
Leukocyte adhesion deficiency (type I)
phagocyte dysfunction
defect in CD18 (LFA-1 integrin, CR3 or CR4) protein on phagocytes -> impaired migration and chemotaxis of neutrophils and poor opsonophagocytosis; autosomal recessive
presentation: recurrent bacterial skin and mucosal infections, absent pus formation, impaired wound healing, delayed separation of umbilical cord
findings: increased num. neutrophils, absence of neutrophils at infection sites
treatment: HSCT
Chediak-Higashi syndrome
phagocyte dysfunction
defect in LYST (lysosomal trafficking regualtor gene) -> microtubule dysfunction in phagosome-lysosome fusion; autosomal recessive
presentation: recurrent pyogenic infections by staphylococci and streptococci, partial albinism, peripheral neuropathy, progressive neurodegeneration, infiltrative lymphohistiocytosis
findings: giant granules in granulocytes and paltelets, pancytopenia, mild coagulation defects
treatment: HSCT
Chronic granulomatous disease
phagocyte dysfunction
defect of NADPH oxidase -> decreased ROS and decreased respiratory burst in neutrophils; X-linked recessive is most common
presentation: increased susceptibility to catalase positive organisms: Nocardia, Pseudomonas, Listeria, Aspergillus, Candida, E coli, Staphylococci, Serratia, B cepacia, H pylori
findings: abnormal dihydrohodamine test (decreased green fluorescence); nicroblue tetrazolium dye reduction test obsolete (not blue)
treatment: antibiotics, neutrophil transfusions, recombinant IFN-gamma to activate macrophages, HSCT
C1 esterase inhibitor deficiency
causes hereditary angioedema due to unregulated activation of kallikrein -> increases bradykinin. ACE inhibitors are contraindicated
autosomal dominant
C1 inhibitor is a protease inhibitor whose target enzymes are C1r and C1s of complement cascade, factor XII of the coagulation pathway and the kallikrein system…unregulated activity can give rise to vasoactive peptides such as bradykinin
treatment: protease inhibitor (kallikrein/bradykinin or plasminogen/plasmin) and danazolol (increases liver production of C1 inhibitor)
C3 deficiency
increases risk of severe, recurrent pyogenic sinus and respiratory tract infections; increases susceptibility to T3 hypersensitivity rxns
C5-C9 deficiencies
terminal complement deficiency increasees susceptibility to recurrent Neisseria bacteremia
DAF deficiency
causes complement-mediated lysis of RBCs and paroxysmal nocturnal hemoglobinuria
Serum sickness
T3 hypersensitivity
an immune complex disease in which antibodies to foreign proteins are produced (takes 5 days). immune complexes form and are deposited in membranes where they fix complement -> leads to tissue damage
mostly caused by drugs acting as haptens - symptoms include fever, urticaria, arthralgia, proteinuria, lymphadenopathy occur 5-10 days after antigen exposure
arthus reaction
a local subacute antibody-mediated hypersensitiviy reaction. intradermal injection of antigen into a presensitized (has circulating IgG) individual leads to immune complex formation in the skin.
characterized by edema, necrosis and activation of complement
test: immunofluorescent staining
graft vs. host disease
type IV hypersensitivity
treatment: corticosterids, methotrexate/cyclophosphamide, cyclosporine, mycophenylate, anti-CD25 (Daclizumab)
multiple sclerosis
type IV hypersensitivity
protein antigens in CNS myeling (myelin basic protein, proteolipid protein)
clinical manifestations: demyelination in CNS with perivascular inflammation; paralysis, ocular lesion
treatment: glucocorticosteroids (immunosuppress), IFN-beta (decrease antigen presentation, increase apoptosis of T cells, increase production of Treg cells and increase production of IL-10 and TGF-beta)
contact dermatitis
type IV hypersensitivity - CTL (CD8+) is the majority
skin inflammation with blisters
ex: poison ivy, nickel allergy
systemic lupus erythematosus (SLE…lupus)
type III hypersensitivity
antibody: anticardiolipin, lupus anticoagulant…antibodies to nucleic acids (ANA, anti-dsDNA)
predominately affects skin and joints - most common presentation is a butterfly rash on the face, low-grade fever, nephritis and nondeforming arthritis
treatment: cyclosporine, methotrexate, azathipurine, hydroxychloroquine, cyclophosphamide, steroids
poststreptococcal glomerulonephritis
type III hypersensitivity
streptococcal cell wall antigens; may be “planted” in glomerular basement membrane
clinical manifestation: nephritis
Goodpasture syndrome
Type II hypersensitivity
anti-basement membrane antibody (and in 60% of patients they may have antibodies to pulmonary alveolar basement membranes) - binds to type IV collagen
clinically characterized by rapidly progressive glomerulonephritis, circulating antibodies and pulmonary hemorrhage
treatment: plasmphoresis, anti-inflammatory and immunosuppressive drugs (like corticosteroids like predisone)
Graves disease
type II hypersensitivity
anti-TSH receptor antibody
this causes hyperthyroidism because the antibodies against the thyroid-stimulating hormone receptor on thyroid epithelial cells stimulate the cells
treatment: plasmaphoresis
myasthenia gravis
type II hypersensitivity
Anti-Ach receptor…this antibody binds to the acetycholine receptor which stops the function of acetylcholine. this does not damage the tissue but causes muscle weakness
some patients may not be able to breathe or swallow - can cause serious complications
rheumatic fever
type II hypersensitivity
target antigen: streptococcal cell wall antigen; antibody cross-reacts with myocardial antigen
mechanism of disease: inflammation, macrophage activation
clinical manifestations: myocarditis, arthritis
systemic sclerosis (scleroderma)
characterized by excessive fibrosis throughout body
skin most commonly affected, but there is widespread damage to small blood vessels and many organ systems are involved
limited scleroderma: only in distal skin and there may be an autoantibody, anticentromere
diffuse scleroderma: seen throughout all parts of the skin. may have an antibody: anti-Scl-70 (anti-DNA topoisomarase I)
Sjorgen syndrome
characterized by dry eyes and mouth resulting from immunologically mediated destruction of the lacrimal and salivary gland
celiac disease
IgA anti-endomysial, IgA anti-tissue transglutaminase
chronic intestinal inflammation and obstruction
can see this on a histo slide because these patients do not have like the villi projections that would allow them to process gluten
treatment: gluten free diet, Anti-TNF-alpha
rheumatoid arthritis
Rh factor (IgM antibody that targets IgG Fc region) and anti-CCP (more specific)
major players are T helper (esp TH17) cells and macrophages
presents as symmetric polyarthritis affecting the small joints of the hands and feet but NOT at the distal pharyngeal joints. will see joint pain and swelling, erosive changes on radiographs, and morning stiffness (like more than an hour to get up and going)
both genetic (HLA-DRB1 shared epitope) and environmental (maybe PPAD and citrullination that occurs via bacterial proteins)
Wegner’s
granulomatosis with polyangiitis
systemic vasculitis that affects the airways, lungs, kidneys, nerves and skin
most often seen in the head and neck
gout
innate immune system recognizes urate crystals and inflammation mediated by inflammasome
over active immune system
periodic fever syndrome
IL-1 - overactive inflammasome response
LAD-2
reduced expression of Sialyl-Lewis, which is a transmembrane protein on leukocytes which allow for extravasation
defects in selectin or selectin ligand expression
treatment: HSCT, antibiotics
Asplenia/splenectomy
increased risk for encapsulated bacteria infection
without the spleen, there is a lack of macrophages. without the macrophages there is no way for the bacteria to be held down and phagocytosized
AIDS
Main symptoms of acute HIV infection: fever, weight loss, malaise, headache, neuropathy, rash, sores in mouth, thrush, myalgia of muscles, enlarged liver and spleen, nausea/vomiting, lymphadenopathy
CD4 lymmphopenia -> allows for opportunistic infections (candidiasis, cytomegalovirus, pneumocystis jiroveci pneumonia, cyryptosporidiosis); wasting syndrome, kaposi sarcoma
AIDs if T cell count is below 200 AND have an aids defining illess (see above)
risk factors: multiple partners, IV drug use
hereditary hemochromatosis
mutation in HLA-A; inherited errors of metabolism
increased uptake of transferrin which leads to accumulation of iron in cells
Prussian blue test
transient hypogammaglobulinemia
found in pedigrees of patients with other immune defects: CVID and SCIDs
clinically present as infants with recurrent upper respiratory infections
erythroblastosis fetalis
also called hemolytic disease of fetus and newborn (HDFN)
ie it is the Rh disease of newborn
type II hypersensitivity
caused by RhD or ABO incompatibility between mother and fetus: erythrocyte antigens present in fetus but not mother enter the maternal circulation, giving rise to maternal antibodies to these antigens which enter the fetus and cause hemolysis
treatment: give mom Rhogam
allergic contact dermititis
Type IV hypersensitivity
CD8+ T cells -> TNF-alpha and Macrophages
drug allergy
type I hypersensitivity
IgE mast cell mediated
sensitization stage - first exposure
second exposure: immediate release of mast cells, then late-phase reaction due to cytokines/arachidonic acid mediators
transfusion reaction
type II hypersensitivity
tissue injury: complement activation, Fc receptor activation on neutrophils and macrophages (IgG1 and IgG3), opsonization of cells
The patient’s serum contains naturally occurring antibodies to the incompatible donor RBCs. They attach to the donor RBCs and induce complement activation that results in generation of the C5-9 membrane attack complex.
food allergy
type I hypersensitivity
IgE mast cell mediated
sensitization stage - first exposure
second exposure: immediate release of mast cells, then late-phase reaction due to cytokines/arachidonic acid mediators
PPD test
Type IV hypersensitivity
DTH response to purified protein derivative; mycobacterial antigen
chronic GvHD
clinical manifestations: dry eyes, stiffness of joints, coarsening of skin; sclerodermatous changes
dysfunction of auto-regulatory T cells leading to self recognition and allo-immune attack
treatment: mainstay glucocorticoids, monoclonal antibody, calcineurin inhibitors and extracorporeal photopheresis
high risk of delayed immune reconstitution
increased susceptibility to infection - most common cause of death
allergic rhinitis
Type I hypersensitivity
increased inflammation and mucus
systemic allergic anaphylaxis
type I hypersensitivity
HIV
DC cells are infected at mucosal site, migrate to lymph node, infect CD4+ T cells; DCs are activated by HIV via TLR7 and TLR8, which increasees IFN-alpha, IL-6, TNF-alpha and IL-12
increased PDL-1 and when this binds PD-1 on T cells, their antigen-specific function becomes impaired
envelope glycoprotein (gp120) binds to cellular receptor CD4; conformational shift, binds a coreceptor, CCR5 or CXCR4
treatment: increase CD4 T lymphocytes by decreasing viral load - antiretroviral therapy can help restore CD4 T helper cell function
diabetes
given the patient presentation with an ulcer/cut on foot that will not heal
underlying immune dysfunction: neutrophils are dysfunctional
anatomical changes due to diabetes: decreased circulation (leads to ulcers) and then decreased neurologic function (leads to loss of sensation; poor recognition of small lesions)
autoimmune polyendocrine syndrome
mutation in AIRE - AIRE normally is responsible for thymic expression of some peripheral tissue antigens in thymus so when this is mutated, the peripherial self-antigens will not be expressed in thymus and the T cells will think self-cells in the body are foreign
autoimmune lymphoproliferative syndrome (ALPS)
T cell tolerance mechanisms
lymphocyte accumulation/proliferation due to impaired apoptosis
mutations in genes involved in FAS signaling (aka the FAS-FAS ligand that tells cells when to undergo apoptosis)
septic shock
sepsis + hypotension that will not respond to IV fluids
septic arthritis
infection of joint space, usually monoarticular (knee, hip and shoulder)
presents as a painful, usually swollen joint accompanied by fever, chills and malaise
treat with parenteral antibiotics and aspiration or surgical drainage
ulcerative colitis
inflammation of the colon
patients present with rectal bleeding, diarrhea and tenesmus
mucosal appearance: edema, friability and confluent ulceration
chronic, recurrent condition
treat with: 5-aminosalicylic acid derivatives, corticosteroids, immunosuppressive therapies and biologic therapies
multiple myeloma
malignant monoclonal gammopathies
is a plasma cell dyscrasia/cancer characterized by the presence of anemia, hypercalcemia, lytic bone lesions and renal failure
leukemia
chimeric antigen receptors/cell based therapies: activate T cells independently of MHC; most successful targeting CD19 for B cell leukemias/lymphomas
bare lymphocyte syndrome
caused by mutations in transcription factors that are required for class II MHC gene expression.
prevents the development of CD4+ T cells. CD4+ T cells are involved in cellular immunity and provide help to B cells, and hence class II MHC deficiency results in combined immunodeficiency.
treatment: hsct
Th1 deficiency
IL-12 receptor
IFN-gammaR1
IL12betaR2
atypical mycobacterial infections
Th17 deficiency
IL-17
chronic Candida albicans and S. aureas infections
C2 and C4 deficiency
increased immune complex disease; cannot activate classical pathway
treatment: hsct
paroxysmal nocturnal hemaglobinuria (PNH)
deficiency in enzyme that creates the glycolipid anchor that tethers DAF and MCP to the membrane
stable membrane-bound C3 convertases
sporadic hemolysis due to spontaneous C3 activation on membranes of RBCs
stevens johnson
occurs within the first few weeks of taking a medication typically for seizure, gout, anti-psychosis
triggered by a medication, pro-drome period (flu like symptoms), then skin lesions and severe mucocutaneous reactions
destroying keratinocytes
mechanism: meds bind to TCR and MHC class I…clonal expansion of CD8 T cells…also recruits NK cells; kills keratinocytes by activating Fas-FasL (ie upregulates apoptosis)
treatment: high dose steroids, IVIG, cyclosporine, plasmaphoresis,
