Immunology Exam 4 Study guide
Type I Hypersensitivity Information:
Mediators:
Histamine
Eosinophil chemotactic factor of anaphylaxis (ECF-A)
Heparin
Neutrophil chemotactic factors
Various proteases
Prostaglandin
Leukotrienes
Platelet activating factor (PAF)
IL-4
Other cytokines
Immune Mechanism
Sensitization
Initial exposure
IgE synthesized
Binds to mast cells and basophils in smooth muscle, blood vessels, and mucosal linings via FceR1 receptors
Activation
Subsequent exposure
Crosslinking of IgE on mast cells and basophils
Degranulation releases mediators
Reaction time
2-30 minutes
Examples:
Anaphylaxis
Type II Hypersensitivity Information:
Mediators:
Cell bound antigen
IgG and IgM
Immune Mechanism:
Ab coats cell surface
C’ activated
cell lysis
opsonization
phagocytosis
Results in cell damage, destruction and dysfunction
Examples:
Blood transfusion reaction
Goodpasture’s
Graves disease
Type III Hypersensitivity Information:
Mediators:
Immune complexes
Immune mechanism:
Ab combines with soluble Ag —> immune complex formation
Deposit in tissue (joints, lungs, skin, kidneys)
Activate C’
Influx of inflammatory cells
Prolongs total inflammatory response
Examples:
Arthus reaction
Rheumatoid arthritis
Lupus
Type IV Hypersensitivity Information:
Mediators
Th1 and Cytotoxic T-cells
Mechanism:
Antigen forms complex with skin proteins
APC presents Ag to Th1
Activated Th1 cells
Release cytokines
Recruit neutrophils
Activate macrophages
Activate cytotoxic T cells
Results in tissue damage
Reaction time:
Sensitization phase — 1-2 weeks after exposure
Subsequent exposure — 48-72 hours after exposure
Examples:
Contact dermatitis
Hypersensitivity pneumonitis
TB skin testing
Autoimmune disease
Loss of tolerance
Women> men
African ethnicity > European ethnicity
Many triggers: hormonal, environmental, infectious
Many systemic manifestations
Organ specific disorders often have/ develop systemic problems
Various lab tests for diagnosis
ANA screening for various autoAb
Autoimmune disorders
Grave’s disease
Overview:
Excess thyroid hormones causing hyperthyroidism
Thyrotoxicosis
Women in 50s and 60s
B-cells produce TRAbs, anti-Tg, anti-TPO
Symptoms:
Nervousness,
agitated
Insomnia
Depression
Weightloss
Rapid Heart beat
Firm goiter
Exophthalmos
Laboratory results for Grave’s Disease
Low TSH
High FT4
Hashimoto’s thyroiditis
Overview
Most common autoimmune dz
Mostly middle-aged women
Immune destruction of thyroid gland produces hypothyroidism
Pathology mediated by activated CD8+ cells
Anti-Tg
and anti-TPO can fix
C’Further tissue damage to thyroid gland
Symptoms of Hashimoto’s Thyroiditis
Fatigue
Dry skin
Puffy face
Swollen eyelids
Weight gain
Brittle hair
Rubbery goiter
Lab results for Hashimoto’s Thyroiditis
Normal or High TSH
Low free T4
Type 1 Diabetes Mellitus (T1DM)
Overview:
Endocrine disorder
Destruction of beta cells
Insulin deficiency
Hyperglycemia
Long term effects:
CVD
Kidney damage
Nerve damage
Lab results:
High glucose levels
Fasting greater than or equal to 126 mg/dl
Oral GTT > 200 mg/dL
Elevated HbA1c > or equal to 6.5%
Celiac Disease
Affects small intestine and triggered by gluten
Symptoms: diarrhea, abdominal pain
Treatment: follow a gluten free diet
HLA-DQ2 or DQ8- positive individuals
AutoAb formed to:
Gliadin (component of gluten)
DGPs ( gliadin peptides)
Endomysium (intestinal tissue)
Multiple Sclerosis (MS)
Inflammation and destruction of axons in the central nervous system
Plaques form in the brain and spinal cord
IgG against myelin basic protein
Stimulates macrophages, microglial cells
Th1 cytokines released
CTLs recruited
Destruction of myelin sheath of axons
Demyelination
Inflammation and injury
Neurodegeneration
Young-middle aged adults (20-50 yrs old)
Women 2x more than men
Symptoms:
Visual disturbances
Weakness in limbs
Dizziness
Sensory abnormalities
Diminished dexterity
Facial palsy
Lab results
Lesions seen on MRI
Increased IgG in CSF
Increased IgG index
Oligoclonal bands on protein electrophoresis of CSF
Myasthenia Gravis
Affects neuromuscular junction
Weak skeletal muscles
Antibodies to acetylchloline receptor (ACHR)
Block binding of ACH to its receptor
Blocks transmission of nerve impulses that activate muscles
Activates C’
Type II hypersensitivity
Symptoms of Myasthenia Gravis
Ptosis (eyelid droop)
Double vision
Corners of mouth droop
Upper body weakness
Difficulty speaking
Difficulty swallowing
Goodpasture’s syndrome
Affects men in 30s
Affects men and women in 60s-70s
Strong genetic association with HLA-DR
autoAb reacts with collagen in glomerular basement of kidneys and alveolar basement of lungs
Activates C’
Attracts neutrophils
Injury/ destruction of membranes
Type II hypersensitivity
Sjogren’s Syndrome
Immune cells damage the glands that make tears and saliva
Secondary form in people with SLE and RA
Patients present with dry eyes, dry mouth, tooth decay
AutoAb (Sjogren’s Syndrome)
anti-SSA
Anti-Sjogren’s-Syndrome-related antigen A
anti-Ro
anti-SSB
Anti-Sjogren’s Syndrome-related antigen B
anti-LA
ANA pattern: fine speckled
Present in 70% of Sjogren’s patients
anti-SSA/Ro and anti-SSB/LA
Present in 24-60% of lupus patients
Present in 70% of Sjogren’s patients
Associated with extreme sun sensitivity and cutaneous SLE
Can cross the placenta
Will cause neonatal lupus
Rash and congenital heart defects
Scleroderma
Inflammation and pain of the skin, muscles, joints, and fibrous tissues
Produce too much collagen
CREST symptoms
Calcinosis
Raynaud’s phenomenon
Esophageal dysfunction
Sclerodactyly
Telangiectasia
ANAs:
Anti-SCL-70
Anti-centromere
Ankylosing Spondylitis
Rheumatic inflammation of spine and sacroiliac joints
Common genetic marker found is HLA-B27
Elevated ESR
Anemia
MAINLY AFFECTS YOUNG MEN
Systemic Lupus Erythematosus (SLE)
Overview:
Chronic systemic inflammatory disease
Multiple organ systems
Targeted Ag are parts of the cell nucleus
AutoAb develop
Anti-dsDNA
Other nuclear components
Lymphocytes
RBCs
Platelets
SLE immunopathology
Dysfunction of apoptosis
Dysfunction in clearing activity
Uncontrolled autoreactivity of T-cells
Polyclonal activation of B-cells
Many immune complexes form
C’ activation — Tissue damage
Complex deposition in tissues
Clinical Symptoms of SLE
Age of onset 20-40 yrs
Women> men
African > European
Joint involvement
Skin rashes (80%)
Renal involvement
Cardiac involvement
Cytopenias
Drug Induced Lupus
Overview:
Different from chronic lupud
Symptoms disappear when drug is stopped
Mild symptoms:
Fever
Rashes
Arthritis
Kidneys rarely involved
Neonatal lupus
Maternal autoAb crosses placenta
Babies born with skin rash and possible congenital heart block
Anti-SSA/Ro and anti-SSB/La
Rheumatoid Arthritis (RA)
Overview:
Chronic erosive arthritis of peripheral joints
Progress to joint deformity and disability
About 25% of patients have osteoporosis
Some patients also develop:
Subcutaneous nodules
Pericarditis
Interstitial lung disease Vasculitis
Immunopathology of RA
AutoAb combine with self-Ag to form immune complex
C’ activated
Immune complex deposition (type III hypersensitivity)
Inflammation destroys the bone and cartilage
Overly active osteoclasts absorb the bone
TNF-a plays a key role in the process
Commonly used medications: methotrexate, mAb to TNF-a
RA autoantibodies
ANAs (speckled) ~ 40% of patients
Rheumatoid factor (FR)
Class of IgM directed to IgG
IgM AutoAb reacts with Fc portion of IgG
Found in ~80% of patients with RA
Not specific for RA
Found in other autoimmune disorders and some chronic disease states
Can cause interference in some IA
Anti-CCP
AutoAb directed against cyclic citrullinated peptide (amino acid)
Performed by ELISA
Highly specific for RA
Not detected in SLE
Can differentiate RA from SLE
Granulomatosis with Polyangiitis (Wegner’s)
Overview:
Inflammation of small to medium sized blood vessels in respiratory tract
Neutrophil activation results in damage to vascular endothelium and a Th1 response
Chronic upper and lower respiratory infections/symptoms
Sinusitis, rhinitis
Nasal and oral ulcers
Gingivitis
Progresses to more systemic disease involving other organs (e.g. kidneys, joints, skin)
Anti-Neutrophil Cytoplasmic Antibodies (ANCA)
Most patients have antibodies to neutrophil cytoplasmic antigen
Proteinase 3 (PR3)
Myeloperoxidase (MPO)
Detected by IIF on ethanol-fixed neutrophils, ELISA, or CLIA
2 patterns: c-ANCA, and p-ANCA
c-ANCA —
Ab to PR3
Diffuse, granular staining in cytoplasm between nuclear lobes
SPECIFIC TO WEGNER’S
p-ANCA —
Ab to MPO
Staining surrounds nuclear lobes, blending together
Seen in ulcerative colitis, vasculitis, and rheumatoid arthritis
Immunoproliferative disorders
Multiple Myeloma: monoclonal gammopathy (IgG), crab features, bone lesions
Waldenstrom’s macroglobinemia: monoclonal gammopathy (IgM), similar to MM but no bone lesions
Immunodeficiency disorders
Transient hypogammaglobulinemia
Maternal Ig decline at 5-6 months
IgG most affected
With or without depression of IgA and IgM
Normal levels of B-cells (CD19)
Delayed maturation of Th cells
Mostly males affected
Pyogenic URI and skin infections
Ig levels normalize spontaneously at 9-15 months
Bruton’s agammaglobulinemia
Presents in infancy
Affects males exclusively
Btk enzyme enzyme required for Ig gene rearrangement in pre-B stage
B cells halted at this stage
No B cells progress past this stage
NO CD19 B-cells in circulation
No plasma cells in lymphoid tissue
No IG of all classes= Agammaglobulinemia
T-cells are normal and abundant
Treated with gamma globulin injections
Selective IgA deficiency
Most common PID ~1 in 500 people
Impaired differentiation to IgA - producing plasma cells
Patients may be asymptomatic or more prone to infections, allergies, and autoimmunity
20% also have IgG2 deficiency
30-40% will produce IgE anti-IgA
Cannot treat with gamma globulin injections
IgG subclass deficiency
IgG heavy chain gene mutations
70% IgG1, 20% IgG2, 6% IgG3, 4% IgG4
Low IgG1 or IgG3
No response to pathogen protein Ag
EX: bacterial toxins
Low IgG2 or IgG4
No response to pathogen polysaccharide Ag
EX: encapsulated bacteria
SCID
Related diseases that affect T- and B- cells
X-linked recessive
Mutation in IL2RG gene — Abnormal signaling, halts maturation
Mutation in JAK3 gene — No Ab production or lymph proliferation
Adenosine deaminase deficiency — Toxic purine metabolites, dec lymphocytes
Most serious of all PID
Presents in early infancy
Any type of infection
Oral yeast infections
Pneumonia
Diarrhea
BM transplant, gene therapy
PNP
Rare; presents in infancy
Enzyme needed to metabolize purines
dec T cells because of purine buildup
Chronic infections
failure to thrive
Some neurological issues
Can be confused with neonatal HIV
Wiscott Aldrich
Rare, X-linked recessive PID
Characterized by
Immunodeficiency
Eczema
Thrombocytopenia
Lethal for children
Infection, hemorrhage, malignancy
Treat with BM transplant or cord blood stem cells
Normal B-cells
T-cells affected
Short platelet half life
Defect in CD43 (WAS gene)
Lab results
Low IgM
ABO blood typing affected
Normal IgA and IgG
High IgE
Low platelet count
Small platelet size
Prolonged bleeding times
DiGeorge Syndrome
Developmental abnormality in 3rd and 4th pharyngeal pouches in embryo
Most patients have deletion in Chromosome 22
Thymus is not developed
Low or absent T-cells
Humoral is NOT affected
Treat with Thymus transplants
Underdevelopment / absence of Thymus
Decreased T cells
Hypoparathyroidism
Hypocalcemia
Tetany — involuntary muscle contractions that are seizure like
Cardiac abnormalities
Mental developmental delay
Abnormal facial features
Severe, recurrent viral infections
Severe, recurrent fungal infections
Ataxia-telangiectasia
Rare autosomal-recessive syndrome
Neurodegenerative disease
Ataxia — involuntary muscle movements
Telangiectasias — capillary swelling and red blotches on skin and/or eyes
Abnormal genes
Errors in gene rearrangement
Combined defect to humoral and cellular Immune system
Poor Ab response
Dec T cells
Low/ no IgG2, IgA, IgE
Improper DNA damage repair
Build up of mutations
Phagocyte enzyme deficiencies
Chronic granulomatous disease (CGD)
Myeloperoxidase (MPO) deficiency
X-linked recessive or autosomal recessive
Often fatal to children
Neutrophils unable to generate oxidative burst
Defect in NADPH oxidase system
Decreased killing of catalase (+) organisms
Recurrent infections, pneumonia, osteomyelitis
Impairs wound healing, abscess
C’ Deficiencies
Most are inherited as autosomal recessive
Early C’ components
Associated with a lupus-like syndrome
C2 deficiency most common
C3 deficiency associated with recurrent infections with encapsulated bacteria
Late C’ components
Associated with Neisseria meningitides infections
Regulatory deficiencies
C1INH, DAF
Transplant Immunology
Classification of Grafts
Autograft — Tissue transfer in the same individual
Example: saphenous vein in cardiac bypass
Syngeneic (Iso) graft — Transfer of cells or tissues to a genetically identical individual
Example: transplant between identical twins
Allograft — Graft between genetically nonidentical individuals of the same species
Example: graft from an unrelated cadaver donor
Xenograft — Transplant between members of a different species
Example: transplant of pig valve into human heart
Types of rejection
Hyperacute:
Occurs minutes to hours after the transplant
Performed antibodies to ABO, HLA, and endothelial antigens bind to vascular endothelium and active C’ and clotting factors
Accelerated:
Occurs few days after the transplant
Mechanisms same as hyperacute
Acute:
Occurs days to months after the transplant
Cytokine production by Th induced delayed-type hypersensitivity (DTH)
CD8+ T cells mediate cytotoxicity
Antibodies fix C’ and induce inflammation
Chronic:
Rejection 1 year or more after transplant
Memory T-cells mediate DTH
Direct v Indirect recognition
Direct:
Cytotoxic T-cells from the recipient bind directly to foreign HLA antigens on the cells of the allograft and release cytotoxic factors
Indirect:
Host APCs present foreign MHC antigens on graft cells to recipient Th cells
May play important role in alloAb production and chronic rejection
HLA genes — MHC class
MHC antigens
Closely linked genes on chromosome 6
Highly polymorphic and induce strong graft rejection
Class I proteins
HLA-A, HLA-B, HLA-C
Expressed on all nucleated cells
Class II proteins
HLA-D (DR,DQ,DP)
Expressed on antigen presenting cells
The HLA system is the most polymorphic genetic system in humans
Grants survival from pathogens encountered
Restricts ability to transplant foreign cells and tissue
HLA proteins are highly immunogenic
Thousands of HLA alleles = many HLA genes = numerous combos
Class I MHC molecule
Heterodimer consisting of polymorphic a- chain non-covalently bonded to B-2 microglobulin
Extracellular region of a-chain is divided into 3 domains
a1, a2, a3
Coded for by HLA-A, B, C
All nucleated cells
Presents intracellular antigen to CD8+ T cells
Class I MHC graft rejection
DIRECT allorecognition
MHC class I expressed on/shed by donor graft
CD8+ T-cells activate and cause cytotoxic cell lysis
Cells on donor graft are destroyed
Graft tissue does not survive in recipient
Class II MHC molecule
Heterodimer consisting of polymorphic a-chain bonded to polymorphic b-chain
a-chain and b-chain have two domains each
a1a2 B1B2
Coded for by HLA-D locus
3 subregions: DR, DQ, DP
Antigen presenting cells
Presents extracellular antigen to CD4+ T-cells
Class II MHC graft rejection
Indirect recognition
Peptides from donor graft are taken in by recipient APC
APC present peptides by MHC class II to CD4+ Th cells
Th1 cells= cellular Immune response
Th2 cells = humoral immune response
Donor cells are destroyed
ABO blood type for transplant
The only blood group system that affects solid organ transplant
Major contingency for blood and blood product trnasfusion (also considered a transplant)
Antibodies strongly bind to RBCs and vascular endothelium, activating C’ cascade = rapid rejection = HYPERACUTE REJECTION
Recipient-donor pairs must be ABO-identical or compatible
Other Histocompatibility systems
Minor Histocompatibility antigens (mHAs)
non-HLA proteins
Also demonstrate amino acid variation
Recorded tissue rejection in MHC-identical transplants
Recorded GVHD in HLA-identical sibling stem cell transplant
CD4 or CD8 T-cells recognize variant protein and mediate Immune Response
Similar to reaction toward microbial antigen
MHC Class I- Related Chain A (MICA)
Polymorphic > 50 allelic variants
Antigens expressed on endothelial cells, keratinocytes, fibroblasts, epithelial cells, dendritic cells, and monocytes
Antigens are NOT expressed on T-cells or B-cells
Anti-MICA antibodies found in 11% of kidney transplant recipients
Rejection and decreased graft survival
GVHD
Lymphoid cells in graft mount immune response against recipient’s histocompatibility antigens
Caused by immune response of T-cells of donor HSC, lung, or liver transplant
Involves massive cytokine release inflammation, and destruction of various tissues (GI tract, skin)
Occurs 100 days or more after a transplant
Type I Hypersensitivity Information:
Mediators:
Histamine
Eosinophil chemotactic factor of anaphylaxis (ECF-A)
Heparin
Neutrophil chemotactic factors
Various proteases
Prostaglandin
Leukotrienes
Platelet activating factor (PAF)
IL-4
Other cytokines
Immune Mechanism
Sensitization
Initial exposure
IgE synthesized
Binds to mast cells and basophils in smooth muscle, blood vessels, and mucosal linings via FceR1 receptors
Activation
Subsequent exposure
Crosslinking of IgE on mast cells and basophils
Degranulation releases mediators
Reaction time
2-30 minutes
Examples:
Anaphylaxis
Type II Hypersensitivity Information:
Mediators:
Cell bound antigen
IgG and IgM
Immune Mechanism:
Ab coats cell surface
C’ activated
cell lysis
opsonization
phagocytosis
Results in cell damage, destruction and dysfunction
Examples:
Blood transfusion reaction
Goodpasture’s
Graves disease
Type III Hypersensitivity Information:
Mediators:
Immune complexes
Immune mechanism:
Ab combines with soluble Ag —> immune complex formation
Deposit in tissue (joints, lungs, skin, kidneys)
Activate C’
Influx of inflammatory cells
Prolongs total inflammatory response
Examples:
Arthus reaction
Rheumatoid arthritis
Lupus
Type IV Hypersensitivity Information:
Mediators
Th1 and Cytotoxic T-cells
Mechanism:
Antigen forms complex with skin proteins
APC presents Ag to Th1
Activated Th1 cells
Release cytokines
Recruit neutrophils
Activate macrophages
Activate cytotoxic T cells
Results in tissue damage
Reaction time:
Sensitization phase — 1-2 weeks after exposure
Subsequent exposure — 48-72 hours after exposure
Examples:
Contact dermatitis
Hypersensitivity pneumonitis
TB skin testing
Autoimmune disease
Loss of tolerance
Women> men
African ethnicity > European ethnicity
Many triggers: hormonal, environmental, infectious
Many systemic manifestations
Organ specific disorders often have/ develop systemic problems
Various lab tests for diagnosis
ANA screening for various autoAb
Autoimmune disorders
Grave’s disease
Overview:
Excess thyroid hormones causing hyperthyroidism
Thyrotoxicosis
Women in 50s and 60s
B-cells produce TRAbs, anti-Tg, anti-TPO
Symptoms:
Nervousness,
agitated
Insomnia
Depression
Weightloss
Rapid Heart beat
Firm goiter
Exophthalmos
Laboratory results for Grave’s Disease
Low TSH
High FT4
Hashimoto’s thyroiditis
Overview
Most common autoimmune dz
Mostly middle-aged women
Immune destruction of thyroid gland produces hypothyroidism
Pathology mediated by activated CD8+ cells
Anti-Tg
and anti-TPO can fix
C’Further tissue damage to thyroid gland
Symptoms of Hashimoto’s Thyroiditis
Fatigue
Dry skin
Puffy face
Swollen eyelids
Weight gain
Brittle hair
Rubbery goiter
Lab results for Hashimoto’s Thyroiditis
Normal or High TSH
Low free T4
Type 1 Diabetes Mellitus (T1DM)
Overview:
Endocrine disorder
Destruction of beta cells
Insulin deficiency
Hyperglycemia
Long term effects:
CVD
Kidney damage
Nerve damage
Lab results:
High glucose levels
Fasting greater than or equal to 126 mg/dl
Oral GTT > 200 mg/dL
Elevated HbA1c > or equal to 6.5%
Celiac Disease
Affects small intestine and triggered by gluten
Symptoms: diarrhea, abdominal pain
Treatment: follow a gluten free diet
HLA-DQ2 or DQ8- positive individuals
AutoAb formed to:
Gliadin (component of gluten)
DGPs ( gliadin peptides)
Endomysium (intestinal tissue)
Multiple Sclerosis (MS)
Inflammation and destruction of axons in the central nervous system
Plaques form in the brain and spinal cord
IgG against myelin basic protein
Stimulates macrophages, microglial cells
Th1 cytokines released
CTLs recruited
Destruction of myelin sheath of axons
Demyelination
Inflammation and injury
Neurodegeneration
Young-middle aged adults (20-50 yrs old)
Women 2x more than men
Symptoms:
Visual disturbances
Weakness in limbs
Dizziness
Sensory abnormalities
Diminished dexterity
Facial palsy
Lab results
Lesions seen on MRI
Increased IgG in CSF
Increased IgG index
Oligoclonal bands on protein electrophoresis of CSF
Myasthenia Gravis
Affects neuromuscular junction
Weak skeletal muscles
Antibodies to acetylchloline receptor (ACHR)
Block binding of ACH to its receptor
Blocks transmission of nerve impulses that activate muscles
Activates C’
Type II hypersensitivity
Symptoms of Myasthenia Gravis
Ptosis (eyelid droop)
Double vision
Corners of mouth droop
Upper body weakness
Difficulty speaking
Difficulty swallowing
Goodpasture’s syndrome
Affects men in 30s
Affects men and women in 60s-70s
Strong genetic association with HLA-DR
autoAb reacts with collagen in glomerular basement of kidneys and alveolar basement of lungs
Activates C’
Attracts neutrophils
Injury/ destruction of membranes
Type II hypersensitivity
Sjogren’s Syndrome
Immune cells damage the glands that make tears and saliva
Secondary form in people with SLE and RA
Patients present with dry eyes, dry mouth, tooth decay
AutoAb (Sjogren’s Syndrome)
anti-SSA
Anti-Sjogren’s-Syndrome-related antigen A
anti-Ro
anti-SSB
Anti-Sjogren’s Syndrome-related antigen B
anti-LA
ANA pattern: fine speckled
Present in 70% of Sjogren’s patients
anti-SSA/Ro and anti-SSB/LA
Present in 24-60% of lupus patients
Present in 70% of Sjogren’s patients
Associated with extreme sun sensitivity and cutaneous SLE
Can cross the placenta
Will cause neonatal lupus
Rash and congenital heart defects
Scleroderma
Inflammation and pain of the skin, muscles, joints, and fibrous tissues
Produce too much collagen
CREST symptoms
Calcinosis
Raynaud’s phenomenon
Esophageal dysfunction
Sclerodactyly
Telangiectasia
ANAs:
Anti-SCL-70
Anti-centromere
Ankylosing Spondylitis
Rheumatic inflammation of spine and sacroiliac joints
Common genetic marker found is HLA-B27
Elevated ESR
Anemia
MAINLY AFFECTS YOUNG MEN
Systemic Lupus Erythematosus (SLE)
Overview:
Chronic systemic inflammatory disease
Multiple organ systems
Targeted Ag are parts of the cell nucleus
AutoAb develop
Anti-dsDNA
Other nuclear components
Lymphocytes
RBCs
Platelets
SLE immunopathology
Dysfunction of apoptosis
Dysfunction in clearing activity
Uncontrolled autoreactivity of T-cells
Polyclonal activation of B-cells
Many immune complexes form
C’ activation — Tissue damage
Complex deposition in tissues
Clinical Symptoms of SLE
Age of onset 20-40 yrs
Women> men
African > European
Joint involvement
Skin rashes (80%)
Renal involvement
Cardiac involvement
Cytopenias
Drug Induced Lupus
Overview:
Different from chronic lupud
Symptoms disappear when drug is stopped
Mild symptoms:
Fever
Rashes
Arthritis
Kidneys rarely involved
Neonatal lupus
Maternal autoAb crosses placenta
Babies born with skin rash and possible congenital heart block
Anti-SSA/Ro and anti-SSB/La
Rheumatoid Arthritis (RA)
Overview:
Chronic erosive arthritis of peripheral joints
Progress to joint deformity and disability
About 25% of patients have osteoporosis
Some patients also develop:
Subcutaneous nodules
Pericarditis
Interstitial lung disease Vasculitis
Immunopathology of RA
AutoAb combine with self-Ag to form immune complex
C’ activated
Immune complex deposition (type III hypersensitivity)
Inflammation destroys the bone and cartilage
Overly active osteoclasts absorb the bone
TNF-a plays a key role in the process
Commonly used medications: methotrexate, mAb to TNF-a
RA autoantibodies
ANAs (speckled) ~ 40% of patients
Rheumatoid factor (FR)
Class of IgM directed to IgG
IgM AutoAb reacts with Fc portion of IgG
Found in ~80% of patients with RA
Not specific for RA
Found in other autoimmune disorders and some chronic disease states
Can cause interference in some IA
Anti-CCP
AutoAb directed against cyclic citrullinated peptide (amino acid)
Performed by ELISA
Highly specific for RA
Not detected in SLE
Can differentiate RA from SLE
Granulomatosis with Polyangiitis (Wegner’s)
Overview:
Inflammation of small to medium sized blood vessels in respiratory tract
Neutrophil activation results in damage to vascular endothelium and a Th1 response
Chronic upper and lower respiratory infections/symptoms
Sinusitis, rhinitis
Nasal and oral ulcers
Gingivitis
Progresses to more systemic disease involving other organs (e.g. kidneys, joints, skin)
Anti-Neutrophil Cytoplasmic Antibodies (ANCA)
Most patients have antibodies to neutrophil cytoplasmic antigen
Proteinase 3 (PR3)
Myeloperoxidase (MPO)
Detected by IIF on ethanol-fixed neutrophils, ELISA, or CLIA
2 patterns: c-ANCA, and p-ANCA
c-ANCA —
Ab to PR3
Diffuse, granular staining in cytoplasm between nuclear lobes
SPECIFIC TO WEGNER’S
p-ANCA —
Ab to MPO
Staining surrounds nuclear lobes, blending together
Seen in ulcerative colitis, vasculitis, and rheumatoid arthritis
Immunoproliferative disorders
Multiple Myeloma: monoclonal gammopathy (IgG), crab features, bone lesions
Waldenstrom’s macroglobinemia: monoclonal gammopathy (IgM), similar to MM but no bone lesions
Immunodeficiency disorders
Transient hypogammaglobulinemia
Maternal Ig decline at 5-6 months
IgG most affected
With or without depression of IgA and IgM
Normal levels of B-cells (CD19)
Delayed maturation of Th cells
Mostly males affected
Pyogenic URI and skin infections
Ig levels normalize spontaneously at 9-15 months
Bruton’s agammaglobulinemia
Presents in infancy
Affects males exclusively
Btk enzyme enzyme required for Ig gene rearrangement in pre-B stage
B cells halted at this stage
No B cells progress past this stage
NO CD19 B-cells in circulation
No plasma cells in lymphoid tissue
No IG of all classes= Agammaglobulinemia
T-cells are normal and abundant
Treated with gamma globulin injections
Selective IgA deficiency
Most common PID ~1 in 500 people
Impaired differentiation to IgA - producing plasma cells
Patients may be asymptomatic or more prone to infections, allergies, and autoimmunity
20% also have IgG2 deficiency
30-40% will produce IgE anti-IgA
Cannot treat with gamma globulin injections
IgG subclass deficiency
IgG heavy chain gene mutations
70% IgG1, 20% IgG2, 6% IgG3, 4% IgG4
Low IgG1 or IgG3
No response to pathogen protein Ag
EX: bacterial toxins
Low IgG2 or IgG4
No response to pathogen polysaccharide Ag
EX: encapsulated bacteria
SCID
Related diseases that affect T- and B- cells
X-linked recessive
Mutation in IL2RG gene — Abnormal signaling, halts maturation
Mutation in JAK3 gene — No Ab production or lymph proliferation
Adenosine deaminase deficiency — Toxic purine metabolites, dec lymphocytes
Most serious of all PID
Presents in early infancy
Any type of infection
Oral yeast infections
Pneumonia
Diarrhea
BM transplant, gene therapy
PNP
Rare; presents in infancy
Enzyme needed to metabolize purines
dec T cells because of purine buildup
Chronic infections
failure to thrive
Some neurological issues
Can be confused with neonatal HIV
Wiscott Aldrich
Rare, X-linked recessive PID
Characterized by
Immunodeficiency
Eczema
Thrombocytopenia
Lethal for children
Infection, hemorrhage, malignancy
Treat with BM transplant or cord blood stem cells
Normal B-cells
T-cells affected
Short platelet half life
Defect in CD43 (WAS gene)
Lab results
Low IgM
ABO blood typing affected
Normal IgA and IgG
High IgE
Low platelet count
Small platelet size
Prolonged bleeding times
DiGeorge Syndrome
Developmental abnormality in 3rd and 4th pharyngeal pouches in embryo
Most patients have deletion in Chromosome 22
Thymus is not developed
Low or absent T-cells
Humoral is NOT affected
Treat with Thymus transplants
Underdevelopment / absence of Thymus
Decreased T cells
Hypoparathyroidism
Hypocalcemia
Tetany — involuntary muscle contractions that are seizure like
Cardiac abnormalities
Mental developmental delay
Abnormal facial features
Severe, recurrent viral infections
Severe, recurrent fungal infections
Ataxia-telangiectasia
Rare autosomal-recessive syndrome
Neurodegenerative disease
Ataxia — involuntary muscle movements
Telangiectasias — capillary swelling and red blotches on skin and/or eyes
Abnormal genes
Errors in gene rearrangement
Combined defect to humoral and cellular Immune system
Poor Ab response
Dec T cells
Low/ no IgG2, IgA, IgE
Improper DNA damage repair
Build up of mutations
Phagocyte enzyme deficiencies
Chronic granulomatous disease (CGD)
Myeloperoxidase (MPO) deficiency
X-linked recessive or autosomal recessive
Often fatal to children
Neutrophils unable to generate oxidative burst
Defect in NADPH oxidase system
Decreased killing of catalase (+) organisms
Recurrent infections, pneumonia, osteomyelitis
Impairs wound healing, abscess
C’ Deficiencies
Most are inherited as autosomal recessive
Early C’ components
Associated with a lupus-like syndrome
C2 deficiency most common
C3 deficiency associated with recurrent infections with encapsulated bacteria
Late C’ components
Associated with Neisseria meningitides infections
Regulatory deficiencies
C1INH, DAF
Transplant Immunology
Classification of Grafts
Autograft — Tissue transfer in the same individual
Example: saphenous vein in cardiac bypass
Syngeneic (Iso) graft — Transfer of cells or tissues to a genetically identical individual
Example: transplant between identical twins
Allograft — Graft between genetically nonidentical individuals of the same species
Example: graft from an unrelated cadaver donor
Xenograft — Transplant between members of a different species
Example: transplant of pig valve into human heart
Types of rejection
Hyperacute:
Occurs minutes to hours after the transplant
Performed antibodies to ABO, HLA, and endothelial antigens bind to vascular endothelium and active C’ and clotting factors
Accelerated:
Occurs few days after the transplant
Mechanisms same as hyperacute
Acute:
Occurs days to months after the transplant
Cytokine production by Th induced delayed-type hypersensitivity (DTH)
CD8+ T cells mediate cytotoxicity
Antibodies fix C’ and induce inflammation
Chronic:
Rejection 1 year or more after transplant
Memory T-cells mediate DTH
Direct v Indirect recognition
Direct:
Cytotoxic T-cells from the recipient bind directly to foreign HLA antigens on the cells of the allograft and release cytotoxic factors
Indirect:
Host APCs present foreign MHC antigens on graft cells to recipient Th cells
May play important role in alloAb production and chronic rejection
HLA genes — MHC class
MHC antigens
Closely linked genes on chromosome 6
Highly polymorphic and induce strong graft rejection
Class I proteins
HLA-A, HLA-B, HLA-C
Expressed on all nucleated cells
Class II proteins
HLA-D (DR,DQ,DP)
Expressed on antigen presenting cells
The HLA system is the most polymorphic genetic system in humans
Grants survival from pathogens encountered
Restricts ability to transplant foreign cells and tissue
HLA proteins are highly immunogenic
Thousands of HLA alleles = many HLA genes = numerous combos
Class I MHC molecule
Heterodimer consisting of polymorphic a- chain non-covalently bonded to B-2 microglobulin
Extracellular region of a-chain is divided into 3 domains
a1, a2, a3
Coded for by HLA-A, B, C
All nucleated cells
Presents intracellular antigen to CD8+ T cells
Class I MHC graft rejection
DIRECT allorecognition
MHC class I expressed on/shed by donor graft
CD8+ T-cells activate and cause cytotoxic cell lysis
Cells on donor graft are destroyed
Graft tissue does not survive in recipient
Class II MHC molecule
Heterodimer consisting of polymorphic a-chain bonded to polymorphic b-chain
a-chain and b-chain have two domains each
a1a2 B1B2
Coded for by HLA-D locus
3 subregions: DR, DQ, DP
Antigen presenting cells
Presents extracellular antigen to CD4+ T-cells
Class II MHC graft rejection
Indirect recognition
Peptides from donor graft are taken in by recipient APC
APC present peptides by MHC class II to CD4+ Th cells
Th1 cells= cellular Immune response
Th2 cells = humoral immune response
Donor cells are destroyed
ABO blood type for transplant
The only blood group system that affects solid organ transplant
Major contingency for blood and blood product trnasfusion (also considered a transplant)
Antibodies strongly bind to RBCs and vascular endothelium, activating C’ cascade = rapid rejection = HYPERACUTE REJECTION
Recipient-donor pairs must be ABO-identical or compatible
Other Histocompatibility systems
Minor Histocompatibility antigens (mHAs)
non-HLA proteins
Also demonstrate amino acid variation
Recorded tissue rejection in MHC-identical transplants
Recorded GVHD in HLA-identical sibling stem cell transplant
CD4 or CD8 T-cells recognize variant protein and mediate Immune Response
Similar to reaction toward microbial antigen
MHC Class I- Related Chain A (MICA)
Polymorphic > 50 allelic variants
Antigens expressed on endothelial cells, keratinocytes, fibroblasts, epithelial cells, dendritic cells, and monocytes
Antigens are NOT expressed on T-cells or B-cells
Anti-MICA antibodies found in 11% of kidney transplant recipients
Rejection and decreased graft survival
GVHD
Lymphoid cells in graft mount immune response against recipient’s histocompatibility antigens
Caused by immune response of T-cells of donor HSC, lung, or liver transplant
Involves massive cytokine release inflammation, and destruction of various tissues (GI tract, skin)
Occurs 100 days or more after a transplant