LECT Diseases of the Immune System I (Singh) Flashcards
Innate Immunity
What is the general function?
What are the cells involved?
What are the proteins involved?
Pre-existing defense against pathogens
Cells: Neutrophils, Dendritic cells, NK cells
Proteins: Complement
Adaptive Immunity
General function?
What are the primary players?
Specific, programmed defense in response to antigen presence
LYMPHOCYTES (+antibodies)
Innate Immunity:
What are examples of physical barriers?
- Skin
- Lining of tracehal bronchial tree
Innate Immunity:
What are examples of chemical barriers?
- Saliva
- Tears
- Acidic pH of stomach
Innate Immunity
What are examples of pattern recognition receptors?
- Toll like receptors
- NOD-like receptors and the inflammasome
- C-type lectin receptors
What are the generative organs of the adaptive immune system?
Bone marrow
Thymus
What are the functions of the generative organs of the adaptive immune system?
-Bone marrow
-Thymus
Bone marrow
-Generation of lymphocyte stem cells
-B lymphocyte maturation
Thymus
- Maturation of T lymphocytes
What are the peripheral organs/tissues of adaptive immunity?
Lymph nodes
Spleen
Mucosa-associated lymphoid tissues [MALT] (tonsils, adenoids, peyer’s pathes)
What are the functions of the peripheral organs/tissues of the adaptive immune system?
Lymph nodes
Spleen
Mucosa-associated lymphoid tissues
Lymph nodes
-Lymphocytes can interact w/ APC’s and antigens in circulating lymph
Spleen
-Lymphocytes can interact with blood-borne antigens
Mucosa-associated lymphoid tissues
-Allow lymphocytes and plasma cells to be in the vicinity of antigens within the mouth and intestinal tract
Identify the structures at the arrows
Where do B cells mature?
Bone marrow
What organ is this?
Thymus
What is the overarching function of the thymus?
T Cell Training
Describe the maturation process of T cells
Cells that are destined to become T cells travel from the bone marrow to the thymus.
These cells start in the cortex, and as they mature, they travel inward toward the medulla (the center).
What is the goal of T cell maturation?
Not attack our own tissues
Teaching the T cells what our own MHC molecules look like, SO THEY DON”T ATTACK
What are the histologic features of the thymus?
Cortex
-TON of lymphocytes
Medulla
-Hassal corpuscles (squamous cell nests)
Describe the events that occur in the lymph node
APC’s interact with lymphocytes
- T and B cell clonal expansion
- B cell differentiation into plasma cells
- Migration of T cells and plasma cells out of lymph nodes and into circulation
T lymphocytes
Give the other name for the following:
Helper
Cytotoxic
Regulatory
Helper : CD4+
Cytotoxic : CD8+
Regulatory : Treg
General function of MHC?
Display peptides for T-cells in adaptive immunity
Describe MHC Class I
Where located?
What do they typically recognize?
How are they processed?
How are they expressed?
Which cells?
ALL nucleated cells (and platelets)
Recognize intracellular antigens (eg viral, tumor)
Processed into peptides by the proteasome
Peptides are transported to the ER, load into the groove of MHC, and the entire complex migrates to the surface
Presentation of complex to CD8+ (cytotoxic) T cells
Describe MHC Class II
Where located?
What do they typically recognize?
How are they processed?
How are they expressed?
Which cells?
Located on APCs
Recognize extracellular antigens (bacterial, allergens)
Processed into peptides by the endolysosomal enzymes
Vesicles form with processed peptides and MHC II complex
Present to CD4+ (Helper) T cells
What is the difference b/w MHC and HLA?
Human leukocyte antigens (HLA) are the Major histocompatibility complex molecules that are present in humans
Which chromosome encodes the HLA molecular structure for a given individual?
Chromosome 6
*Remember: there are 6 regions we care about.
- HLA-A
- HLA-C
- HLA-B
- HLA-DR
- HLA-DQ
- HLA-DP
How many HLA alleles are there?
1000’s
The diversity of HLA haplotypes inherently causes differences in the pouplation in terms of:
Fighting off illness
Allergic sensitivities
How are HLA haplotypes clinically important?
Must consider with:
- Transplanted organs
- Associated autoimmune diseases
Summarize cell-mediated immunity
APC’s bring back pathogens while expressing MHC-associated peptide antigens
Recognized by T cells to elicit targeted response via:
- Proliferation
- Differentiation
- Migration
- Killing
MHC Class I
Kill what?
By what cells?
Intracellular pathogens
CD8+ cells
MHC Class II
Kill what?
By what cells?
Extracellular pathogens
CD4+ recruitment of macrophages and other T lymphocyte subsets
Antibodies come from _________
Which come from _________
Antibodies come from plasma cells
Which come from B lymphocytes
In order for the humoral immune response to be fully functional, you need the ___________ to be intact
Helper T Cells
What are the two aspects of humoral immunity that are T cell dependent?
Isotype switching
Increasing affinity
Antibody Class Features
IgM
The first Ig produced
Pentamer — REALLY BIG
Does NOT cross the placenta
Antibody Class Features
IgG
- Longest half life
- Important in fetal protection
- Crosses the placenta
Antibody Class Features
IgA
Mucosal defense
Present in high levels in the colostrum (first breast milk produced by mom)
Antibody Class Features
IgE
-Shortest half life
_-_Regulates hypersensitivity reactions
-High affinity binding to FC receptor on mast cells, basophils, eosinophils
NK cell – innate immunity
Descibe the activity of NK cells
Activity of NK cells is regulated by activating and inhibiting MHC Class I receptors
Healthy cells will present MHC Class I and will NOT be destroyed by NK cells
Damaged cells will not express MHC Class I and WILL be desstroyed by NK cells
Describe clonal selection
- Lymphocytes are killed if they recognize self antigens (clonal deletion)
- Best suited lymphocytes that can detect a pathogenic antigen will be selected to be clonally expanded
Define:
Hypersensitivity reaction
An immune reaction to foreign or self antigens that are
Excessive
Harmful
What are the 4 mechanisms of hypersensitivity reactions?
What are examples of OBVIOUS hypersensitivity reactions that you can idendify based on presentation?
- Anaphylaxis
- Asthma attack
- Granuloma
What are examples of SUBTLE hypersensitivity reactions that require you know what is happening immunologically to diagnose?
- Goodpasture syndrome
- Lupus erythematosus
- Type 1 DM
What is included in a Type I Hypersensitivity reaction?
Seasonal allergies
Asthma
Food allergies
Severe allergic reactions (urticaria, angioedema, anaphylaxis)
What happens PRIOR to a Type I Hypersensitivity reaction occuring (behind the scenes)?
DC’s present antigen to naive T cells
T cells differentiate to Th2 cells
B cells class switch to IgE
Mast cells get prepared by binding IgE to specific Fc(epsilon)RI receptor
After the priming step for Type I hypersensitivity, what happens with a repeat exposure to the allergen?
Mast cell activation:
Degranulation (Histamine)
Lipid mediators (Leukotrienes B4, C4, D4, prostaglandin D2, platelet activating factor)
What are (3) clinical manifestations of mast cell activation?
Bronchoconstriction
Bowel peristalsis increases
Vasodilation permeability increases
What are the two phases of a Type I Hypersensitivity reaction?
Immediate reaction
Late reaction
What is occuring in the immediate reaction of a Type I Hypersensitivity reaction?
Mast cell mediators are active!!!
Vasodilation
Vascular leakage
Smooth muscle spasm
What is occuring in the late reaction of a Type I Hypersensitivity reaction?
Inflammatory cells are active!!!
Eosinophils
Basophils
Neutrophils
*Epithelial damage
What is this?
Eosinophilic esophagitis
- Food allergy
- Recurrent dysphagia
- Weight loss (hurts to swallow)
How do you determine the allergen that is causing an allergic reaction?
Skin prick testing
Describe what a Type II Hypersensitivity Reaction is:
Reactions where antibodies directly react with antigens present on the cell surface or extracellular matrix
How many mechanisms are there for Type II Hypersensitivity?
What are they called?
3
A. Opsonization and phagocytosis
B. Complement (inflammation)
C. Antibody-mediated cellular dysfunction
Describe the:
Opsonizatinon and phagocytosis
Mechanism of a Type II hypersensitivity reaction
Opsonization leads to phagocytosis
Basic mechanism: no cells!
Anemia, thrombocytopenia
Describe the:
Complement
Mechanism of a Type II hypersensitivity reaction
Basic mechanism = Damaged Tissue!
Inflammation and tissue injury caused by neutrophils
Describe the mechanism of rheumatic heart disease
Combination of Type II hypersensitivity rxn and molecular mimicry
Body is attacking cardiac tissue mistakingly thinking it is streptococcal antigen
Describe the:
Antibody-mediated cellular dysfunction
Mechanism of a Type II hypersensitivity reaction
Basic mechanism = Dysfunction due to receptor blockade
- Disrupted endocrine signaling
- Disrupted neural signaling
Describe Type III Hypersensitivity reaction mechanism
Antigen-antibody complexes form and deposit causing damage
Which form of hypersensitivity is commonly associated with “Serum sickness”?
Type III
Which is Type II vs Type III?
What is the mechanism of Type IV hypersensitivity reactions?
T-cell mediated!!!
CD4+ responds by: releasing cytokines and inducing inflammation
CD8+ responds as a cytotoxic agent against antigens on surface of target cell
What is a VERY COMMON DISORDER that is a type IV hypersensitivity reaction?
Type I DM
What is the major hallmark of a Type IV hypersensitivity reaction?
Granuloma!!!
Tuberculosis test : the Mantoux test is an example of a
Hypersensitivity type ______ reaction
IV
Rapid fire Hypersensitivity types:
Anaphylaxis and Asthma attack
Type I
Rapid fire Hypersensitivity types:
Granuloma
Type IV
Rapid fire Hypersensitivity types:
Goodpasture syndrome
Type II
Rapid fire Hypersensitivity types:
Lupus Erythematosus
Type III
Rapid fire Hypersensitivity types:
Type 1 DM
Type IV
What is central tolerance?
T cells have learned to tolerate self-antigens
Learned prior to release from generative lymphoid organs
What is peripheral tolerance?
T cells have learned to tolerate self-antigens;
Ongoing regulation in peripheral tissues
What are examples of inhibitory receptors on T lymphocytes?
CTLA
PD-1
How do tumors and viruses utilize inhibitory receptors on T cells to their advantage?
By using the CTLA/PD1 inhibitory receptors when tumors and viruses bind, it effectivley silences the T cell from destroying it
How is blockade of PD-1/CTLA-4 signaling useful clinically?
TUMOR IMMUNOTHERAPY
T regulatory cells are…
Foxp3+
AIRE gene
What is the purpose of AIRE, and where does it exert its normal function?
What normal process would fail in the basence of normal AIRE?
(Autoimmune regulator)
Purpose of AIRE = Stimulates expression of some “peripheral tissue-restricted” self antigens in the thymus and is thus critical for deletion of immature T cells specific for these antigens.
Abnormal AIRE= would cause an Autoimmune polyendocrinopathy
IPEX
What does IPEX stand for?
What mutation is involved?
What normal process fails in this disease?
IPEX = Immune dysregulation, polyendocrinopathy, enteropathy, X linked
Mutation = FOXP3
Process that fails = Dysfunction of Treg cells
What is an autoimmune disease?
An immune reaction is directed against a self-antigen
That immune reaction is primarily responsible for a pathologic condition
There is no other pathophysiology responsible
What is ankylosing spondylitis?
Genetically inherited inflammatory condiiton of the joints, particularly the spine
Inflammation leads to degeneration and then fusion of the vertebrae
What specific genetic mutation is ankylosing spondylitis associated with?
Class I HLA allele B27
What is the specific gene associated with Crohns disease?
NOD-2 gene
Describe how epitope spreading develops in oral lichen planus?
Initial T cell response leads to keratonic lesions in oral and conjunctival mucosa –>
Basement membrane disruption exposes NEW antigenic proteins –>
A secondary B cell response occurs
What does ANA stand for?
Anti nuclear antibody
What is an ANA test useful for clinically?
ANA is a sensitive test for multiple autoimmune diseases
If (+), can prompt more specific testing to confirm the particular diagnosis
What would:
Homogenous
Speckled
Nucleolar
Centromere
ANA staining patterns look like?
Lupus is an autoimmune disease associated with:
What are the tendencies for Lupus in terms of affliction?
VAST ARRAY of autoantibodies
Genetic association: HLA-DQ
Female bias
UV light
What are clinical manifestations of Lupus?
Malar rash (aka butterfly rash)
Discoid rash
Hemolytic anemia
Arthritis
Skin rashes
(Tendency toward younger females)
What is the most common pattern of Lupus nephritis?
Diffuse Lupus Nephritis (Class IV)
Diffuse Lupus Nephritis (Class IV)
Describe what you would see histologically:
Globeruli show increased cellularity
Proliferation of endothelial, mesangial and epithelial cells
Skin changes in SLE
Describe histoligically what you would see:
Malar Rash
Basal layer degeneration of the skin
As squamous skin cells degenerate, start to see WHITE (indicates damage)
What is a major cardiac manifestation of Lupus?
Libeman-Sacks endocarditis
What is an L-E cell?
A neutrophil or macrophage that ingests the nucleus of a damage cell
(Historically, USED to be used to diagnosis of Lupus, but not anymore!)
Describe the features of Discoid Lupus
Typically just the face and scalp are affected
(+) ANA
(-) Anti-DS DNA
What is Drug-induced lupus?
Medication-induced breakdown of self tolerance
(Procainamide, hydralazine)
Drug induced lupus is
POSITIVE for what?
Positive ANA
Positive Anti-Histone Ab
What are the high risk HLA linkages in drug induced lupus?
Hydralazine confers high risk for DIL w/ HLA-DR4 allele
Procainamide confers high risk for DIL w/ HLA-DR6 allele
What is Sjogrens syndrome?
Autoimmune disease resulting in destruction of lacrimal and salivary gland tissue
What are clinical manifestations of sjogren syndrome?
Dry eyes
Root caries
Oral thrush
How do you diagnose sjogren syndrome?
Use Anti-Ro/SS-A and Anti-La/SS-B tests
or
Biopsy of the lip to look for inflammation of minor salivary gland tissue
What are the two major complications associated with sjogren syndrome?
Pulmonary fibrosis
Lymphoma
What is systemic sclerosis?
FIbrosis throught the WHOLE body!!!
Describe the histologic changes you would see in systemic sclerosis
(Left) = normal
(Right) = systemic scelerosis
Lack of fatty layer, vascular hyalinization
What would you be able to readily see in a patient with systemic sclerosis?
Also state
- the type of staining you would use
- Disease process associated with each
A little trick to remember these:
Speckled : Systemic Sclerosis
_C_entromere: _C_REST syndrome
What is CREST syndrome?
Unique form of limited sclerosis w/ additional features
Mixed Connective Tissue Disease
High titer for?
Common presenting feature?
Anti-ribonucleoprotein (RNP)
Raynaud phenomenon
What is the uniting pathophysiology of IgG4-related disease?
IgG4-producing plasma cells
T lymphocytes –> fibrosis
Which leads to eventual fibrotic scarring and irreversible damage to involved areas
GOOD JOB
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