Immunology Flashcards
(184 cards)
1
Q
What are the characteristics of innate immunity?
A
- Present at birth
- Rapid
- Relies on pattern recognition
- Not specific
- No memory
- Primarily mediated by neutrophils
2
Q
What are the characteristics of adaptive immunity?
A
- Slow (on first exposure)
- Diverse
- Adapts to antigen (not pre-formed)
- Highly specific
- Generates memory and improved immunity w/ repeated antigen exposure
3
Q
Which immunoglobulin do all very young infants (under 6 weeks) have?
A
Maternal IgG
(And Maternal IgA if they are nursing)
4
Q
Which sort of immune response do older adults and infants have a decreased ability to generate?
A
T-cell independent B cell response
5
Q
What is the role of neutrophils in innate immunity?
A
Neutrophils (granulocytes, PMNs)
- First responders
- Rapidly migrate from bone marrow to blood to tissue (peripheral blood neutrophilia)
- Engulf/kill pathogens
- Release additional pro-inflammatory cytokines
- Major cell of acute inflammatory response
- Do not present antigen on MHC class II
6
Q
Where are mast cells present?
What are mast cells activated by?
What do mast cells release?
A
Mast cells
- Present throughout connective tissue
- Activated by trauma, complement proteins (C3a and C5a), and cross-linking of IgE (which is bound by IgE Fc receptor)
- Express-toll like receptors that recognize bacteria and viruses
- Release histamine and other mediators of inflammation
7
Q
What does C3b do?
A
Acts on C5 to make C5a and C5b
8
Q
What does C5b do?
A
Inserts into cell membrane of pathogen and is bound by C6, C7, C8, and C9 to make the membrane attack complex
9
Q
What does the membrane attack complex do?
Which bacteria are particularly susceptible?
A
Forms a hole in the membrane causing the pathogen to lyse
Gram-negative bacteria are particularly susceptible
10
Q
Describe the classic pathway of complement activation
A
C1 binds to the constant fragment of IgG or IgM (antigen-antibody complex)
11
Q
Describe the alternative pathway of complement activation
A
Microbial products directly activate complement
12
Q
Describe the lectin pathway of complement activation
A
Mannose-binding lectin (serum protein) binds carbohydrate antigens on the surface of micro-organisms (such as encapsulated bacteria)
13
Q
What is the function of C3a?
A
Triggers mast cells to degranulate and release histamine (anaphylatoxins)
14
Q
What are the functions of C5a?
A
- Triggers mast cells to degranulate and release histamine (anaphylatoxins)
- Chemotactic for neutrophils
15
Q
On which cells is CD14 expressed?
What is the function of CD14?
A
Monocytes/macrophages
Co-receptor for TLR4 that recognizes LPS
16
Q
What elements of innate immunity might defend against infection by bacteria in the GI tract?
A
- Intact mucosal epithelium
- Mucous
- pH
- Microbial molecules such as defensins
- Macrophages
- Dendritic cells
17
Q
What is the cause of chronic granulomatous disease?
What do patients suffer from?
A
Caused by a defect in NAPDH oxidase and failure to produce hydrogen peroxide and kill bacteria
Patients have recurrent infections from catalase-producing organisms
18
Q
What are the stages of repair in healing by first intention?
A
- Hemorrhage and formation of a blood clot
- Acute inflammation
- Proliferation of the epithelial cells
- Organization of the wound
- A scar composed of connective tissue w/ scant inflammatory cells
19
Q
What are the differences between healing by secondary intention to healing by first intention?
A
In healing by secondary intention,
- The clot is larger
- Inflammation is more intense
- There is more granulation tissue with greater likelihood of complications
- Wound contraction occurs due to myofibroblasts
20
Q
What is the major cytokine involved in fibrosis?
A
TGF-beta
21
Q
Mutations in RAG1 or RAG2 can cause which immune disorder?
A
SCID
22
Q
What two types of diversity do B cell receptors have?
A
Combinatorial diversity
Junctional diversity
23
Q
What is combinatorial diversity?
A
Somatic recombination of the V and J gene regions occurs for antibody light chain variable regions and V, D, and J antibody regions for the heavy chain variable regions
Mediated by VDJ recombinase, RAG genes
24
Q
What are the characteristics of junctional diversity?
A
- Nucleotides are added and removed during recombination
- Occurs at the joining ends of the gene segments
- Significantly increases diversity of the VDJ and VJ regions
- Known as hypervariable regions
25
What are the stages in B cell development with regards to the B cell receptor?
1. Pro-B cell has no heavy chains
2. Pre-B cell has cytoplasmic mu heavy chains and is pre-BCR, successful gene rearrangement of mu heavy chain
3. Immature B cell has IgM surface BCR, successful gene rearrangement of the light chain (kappa or lambda)
4. Naive B cell has IgM, IgD surface BCR
26
How does the pro-B cell to pre-B cell transition occur?
Successful gene rearrangement of the mu heavy chain
27
How does the pre-B cell to immature B cell transition occur?
Successful gene rearrangement of the light chain (kappa or lambda) which allows for expression of an IgM BCR
28
What causes X-linked agammaglobulinemia?
What does a patient with X-linked agammaglobulinemia experience?
Mutation in Bruton's tyrosine kinase (cannot go from pre-B cell to immature B cell)
Markedly decreased B cells, low antibodies of all types, no tonsils
29
How does CD21 serve as a second signal for B cells?
CD21 interacts with the C3d complement component bound to antigen (alternative complement pathway)
Enhances B cell activation ~1000 fold
30
What are the functions of follicular dendritic cells?
* Capture complement/antigen complexes on the cell surface
* Present antigen complexes to B cells and allow selection for B cells with higher affinity/avidity antibodies
31
What does T cell co-stimulation cause B cells to undergo?
What occurs in this process?
Somatic hypermutation in the germinal center
Antibody variable regions are subject to random point mutations (activation-induced cytidine deaminase [AID])
Some of the mutations give rise to higher affinity/avidity antibodies which are selected for by FDCs and T cell interactions
32
What is affinity maturation?
The process of selection for increased affinity/avidity in B cells in the germinal center
This occurs after B cells have undergone somatic hypermutation in the germinal center
33
What are CD79a and CD79b?
B cell receptor associated proteins (Ig-alpha, Ig-beta) involved in signal transduction after antigen crosslinking
Their activation leads to phosphorylation of ITAMs to trigger downstream signaling pathways
34
On an individual naive B cell expressing both IgM and IgD surface antibody, which regions of the surface IgM antibodies are identical to the surface IgD antibody?
Variable regions of both heavy and light chains are identical between the IgM and IgD antibody
B cells only express one heavy chain variable region and one light chain variable region, even when the constant regions differ
35
How do CD8+ Cytotoxic T-cells kill their prey?
2 methods
1. Production of cytotoxic molecules like perforin or granzyme
2. Expresion of FasL (induces apoptosis when binding to the Fas protein)
36
Which complement protein first recognizes antigen-antibody complexes in the classic pathway?
C1
(C**1** = the **#1** antigen-antibody recognizing protein)
37
Which complement proteins trigger mast cells to degranulate and release histamine?
C3a, C5a
38
Which complement protein is chemotactic to neutrophils?
What does this mean?
C5a
Chemotactic = ~attractive~
C5a recruits neutrophils
39
Which complement protein opsonizes bacteria?
C3b
40
What is TLR4?
What does it do?
TLR4 = Toll-like receptor 4
Recognizes LPS on the surface of gram negative bacteria
(Works together with CD14 expressed by monocytes and macrophages to recognize LPS)
41
1. What is RIG-1 helicaase
2. Where is it found?
3. What does it do?
1. RIG-1 helicase is a pattern recognition protein that recognizes intracellular pathogens
2. RIG-1 helicase is found in cytoplasm of immune-competent cells
3. RIG-1 helicase recognizes nucleic acids of viruses
42
Which cytokine recruits neutrophils?
IL-8
A pro-inflammatory cytokine
43
What is Sialyl Lewis X?
What process is it involved in?
Sialyl Lewis X is a protein expressed constituitively on the surface of neutrophils
It binds to P-selectin in E-selectin in the "rolling" step of phagocytic cell recruitment and migration
44
*S. pyogenes* secretes C5a peptidase
Describe the effect of C5a peptidase on phagocytic cell recruitment and migration
C5a peptidase destroys C5a, which is a chemokine for neutrophils
Without C5a, neutrophils chemotaxis will be decreased; they won't be able to effectively move toward the site of inflammation
45
A patient has had multiple, recurrent bacterial infections without appropriate pus formation.
What might be the problem?
What evidence would support your diagnosis?
This patient might have Leukocyte Adhesion Deficeincy (LAD), due to a defect in the CD18 subunit of integrins. As a result, neutrophils cannot escape from blood vessels to get ot the tissue (Neutrophils can't adhere to endothelium = they can't undergo diapedesis)
Normal to high neutrophil count in the peripheral blood would support your diagnosis
46
A defect in NADPH oxidase leads to...
Chronic granulomatous disease
* Defective NADPH oxidase
* -\> Failure to produce hydrogen peroxide
* -\> Cannot make hypochlorite ion
* Cannot kill bacteria effectively
47
A patient has a history of recurrent infections from catalase (+) bacteria with the formation of multiple granulomas
What might be the problem?
Chronic granulomatous disease;
A defect in NADPH oxidase results in downstream failure to produce the hypochlorite ion from hydrogen peroxide;
Hydrogen peroxide alone is not effective at killing catalase (+) bacteria, because these bacteria can break down hydrogen peroxide.
48
When does the complement binding region of an AB/BCR become accessible?
Why?
When antigen binds
Only want complement active when immune response is necessary
49
What are the two parts of the Fc region of an antibody?
Complement binding region
Phagocyte binding region
50
Compare and contrast the T cell dependent and T cell independent responses in terms of chemical nature, isotype switching, affinity maturation, memory, and location
51
Describe the steps of the antibody response to a T cell dependent antigen for antigen-activated B cells in the B cell-T cell zone border outside germinal center
* Interact with antigen-activated CD4+ T helper cells
* Differentiate to short-lived plasma cells (plasmablasts)
* Produce and secrete IgM antibody
* Antibody is low affinity for antigen
52
Describe the steps involved in feedback inhibition of humoral immunity
IgG production leads to feedback inhibition
* FcyRIIB on surface of B cells
* Binds Fc portion of IgG
* Signals through immunomodulatory tyrosine-based inhibition motif (ITIM)
* Terminates B cell response to antigen
53
A male patient presents with present but low levels of all classes of immunoglobulins at age 15. What types of infections is he at risk for?
Is it possible he has SCID?
He has CVID, so he is at risk for bacterial infections, Giardia, and enterovirus
He does not have SCID. SCID presents in infancy and is life-threatening without therapy. SCID involves an almost complete absence of the adaptive immune response and no immunoglobulins (and almost no B cells, no T cells +/- NK cells)
54
What kind of selection occurs on T cells in the cortex of the thymus?
Positive selection
55
What kind of selection occurs on T cells in the medulla of the thymus?
Negative selection
56
Where does the first step of thymic T cell selection occur?
Thymic cortex
57
Where does the second stage of thymic T cell selection occur?
Thymic cortex
58
Describe positive selection in the double positive stage of thymic T cell selection
Cortical epithelial cells express MHC class I and class II molecules
A T cell will survive if the TCR with CD4 or CD8 binds weakly to the self-MHC molecules
(Occurs in cortex)
59
Where does the third stage of thymic T cell selection occur?
Thymic medulla
60
What is the third stage of thymic T cell selection?
CD4+ or CD8+ (single positive) stage
61
What sort of selection occurs in the single positive stage of thymic T cell selection?
Negative selection
62
Describe negative selection in the single positive stage of thymic T cell selection
* Cortical epithelial cells express MHC class I and II molecules
* Autoimmune regulator (AIRE) transcription factor synthesizes self proteins to be expressed in the MHC molecules
* Strong binding of the TCR to self-antigen/MHC molecules -\> cell death or becomes regulatory T cell
* Weak/no binding of the TCR to self-antigen/MHC molecule -\> survive and go to the periphery
63
In the single positive stage of thymic T cell selection, what occurs if the TCR binds strongly to the self-antigen/MHC molecule?
T cell death or becomes regulatory T cell
64
In the single positive stage of thymic T cell selection, what occurs if the TCR binds weakly/not at all to the self-antigen/MHC molecule?
T cell survives and goes to the periphery
65
Diagram the steps in T cell development
66
What tissue is this?
What are the correct labels for the two arrows?
Thymus
67
What produces self-peptides that are used in negative selection during thymic selection of T cells?
Autoimmune regulator (AIRE)
68
What is deficient in people with DiGeorge syndrome?
Marked deficiency in T cells, bc no thymus
69
What lab finding do people with DiGeorge syndrome exhibit besides low T cell count?
Why?
Hypocalcemia
Due to lack of parathyroid glands
70
Some patients with DiGeorge syndrome (thymic aplasia) have decreased serum antibodies and recurrent pyogenic infections. Why might this occur if the B cells develop normally?
Lack of CD4+ T cells to support B cell antibody production
71
What cells do people with RAG deficiency lack?
Which cells do they have?
No B or T cells
Normal NK cells
72
What occurs when T cells repeatedly encounter high levels of self-antigen in the periphery?
Clonal deletion through apoptosis
(Tregs also participate in suppressing self-reactive T cells)
73
With regards to the first signal of CD4+ T cell activation, what does longer duration of antigen binding lead to?
More phosphorylation of ITAMs
74
What are the major components involved in the first signal of CD4+ T cell activation?
Antigen, TCR (MHC), ITAMs, ZAP70 tyrosine kinase
75
What is the second signal in CD4+ T cell activation?
Binding of activating co-stimulatory molecules (to CD28) or cytokines
76
What is the usual co-stimulatory receptor in the second signal of CD4+ T cell activation?
CD28
(cytokines binding to cytokine receptors can also provide second signal)
77
What is the first signal in activation of CD8+ cytotoxic T cells?
TCR and co-receptor CD8 recognize and bind the peptide in MHC class I
78
What is the second signal in activation of CD8+ cytotoxic T cells?
Cytokines (IL-2) secreted from CD4+ cells or co-stimulatory molecule engagement
79
When T cells are activated, what do T cells upregulate expression of?
* IL-2 (T cell growth factor)
* IL-2R
(Autocrine effect of IL-2 binding to IL-2 receptor allows clonal growth and proliferation of antigen-specific activated T cells)
80
When are the T cell inhibitory molecules upregulated?
48-96 hours after initial T cell activation
81
How does CTLA-4 inhibit T cells?
Binds to B7 -\> blocks binding of B7 to CD28 -\> inhibits IL-2 synthesis
82
How does PD1 inhibit T cells?
PD1 interacts with its receptor PDL1 on APCs (macrophages and dendritic cells) -\> inhibits immune response
83
What are two examples of superantigens?
Staphylococcal enterotoxins
Toxic shock syndrome toxins
84
What is the effect of superantigen binding directly to TCR and MHC class II protein without internal processing?
Activates multiple T cells at once regardless of TCR antigen specificity
Uncontrolled release of cytokines from T cell and APC (IL-2, IL-1, and TNF)
Contributes to illness
85
What occurs when memory T cells have a subsequent recognition of antigen?
* Activation with a lower level of co-stimulation
* Rapid and more robust production of cytokines
86
What is the function of IL-12?
* T cell growth factor
* Stimulates TH1 subset of CD4+ T cells
87
What is the function of IL-13?
Activates eosinophils
88
What is the function of IL-17?
Promotes neutrophilic inflammation
89
What are the functions of INF-gamma?
* Stimulates phagocytosis by macrophages
* Increases expression of MHC class I and II
* Promotes TH1 T cell response
* Inhibits TH2 CD4+ T cell response
90
In most cases of hypersensitivity, what is true?
Immune system has seen the antigen (or closely related antigen) before
91
Which type(s) of hypersensitivity is/are antibody mediated?
Types I, II, and III
92
Which type(s) of hypersensitivity is/are T cell mediated?
Type IV
93
What cells and antibodies are involved in Type I hypersensitivity?
* Mast cells and basophils
* Preformed IgE (prior B cell response driven by TH2 helper T cells)
94
What is the mechanism of Type I hypersensitivity?
* First exposure sensitization to form IgE antibodies
* Subsequent exposure: IgE binds antigen and crosslinks mast cell Fc receptors
* Mast cells release preformed mediators (histamine) and produce additional mediators
95
What are examples of Type I hypersensitivity?
* Anaphylaxis
* Allergic rhinitis
* Asthma
* Hives
96
What is Type II hypersensitivity also known as?
Cytotoxic/antibody-mediated
97
What cells and antibodies are involved in Type II hypersensitivity?
* CD8+ cytotoxic T cells
* NK cells
* Neutrophils
* Preformed IgG/IgM (produced by B cells, driven by TH2 CD4+ helper T cells or naturally occurring)
98
What is the mechanism of Type II hypersensitivity?
* Preformed IgG or IgM antibody binds to fixed cell surface or extracellular matrix antigens
* Binding leads to complement activation and opsonization/phagocytosis and/or antibody-dependent cell-mediated cytotoxicity (ADCC) by NK or CD8+ cytotoxic T cells
99
What are examples of type II hypersensitivity?
* Some drug allergies
* Incompatible blood transfusions
* Rh hemolytic disease of newborn
* Rheumatic fever
* Goodpasture's syndrome (antibody against basement membrane)
100
What is Type III hypersensitivity also known as?
Immune complex-mediated
101
What is the mechanism of Type III hypersensitivity?
* When antigen is abundant, soluble immune complexes (antigen bound to antibody) form and deposit in tissues (particularly in vessels)
* Immune complex deposition can activate complement and lead to inflammation (chemotaxis of neutrophils, vessel leakage, and vessel damage)
102
Which types of hypersensitivities involve the activation of complement?
Type II and Type III
103
What are examples of Type III hypersensitivity?
* Serum sickness (e.g. rxn to proteins in serum from a non-human source)
* Systemic lupus erythematosus
* Arthus reaction: local injection of antigen that reacts with preformed IgG
104
What can be used to visualize immune complex deposition from a Type III hypersensitivity?
Anti-IgG immunofluorescence
105
What is Type IV hypersensitivity also known as?
Delayed-type hypersensitivity
106
What cells are involved in Type IV hypersensitivity?
* Antigen-presenting cells
* TH1 CD4+ helper T cells
* Sometimes CD8+ cytotoxic T cells
(no antibodies involved)
107
In Type IV hypersensitivity, what sort of response do antigen-presenting cells drive?
TH1 CD4+ helper T cell response
108
Which type hypersensitivity is involved in granuloma formation?
Type IV hypersensitivity
109
What are examples of Type IV hypersensitivity?
* Mycobacterium tuberculosis and PPD
* Graft vs. host disease
* Contact dermatitis
110
What type of hypersensitivity is contact dermatitis?
In contact dermatitis, what do the T cells recognize?
Type IV hypersensitivity
T cells recognize chemically modified self proteins
111
What does a positive PPD test indicate?
TB infection or prior BCG vaccine
112
What cells does M. tuberculosis / PPD involve?
CD4+ T helper cells and macrophages
113
What type of hypersensitivity is this?
How do you know?
Type IV hypersensitivity
This is predominantly a lymphocyte response (type IV hypersensitivity is cell-mediated)
114
List the stages of B-cell development
1. Early hematopoietic stem cell
2. Lymphocyte progenitor
3. Pro B-Cell
4. Pre B-Cell
5. Immature B-Cell
6. Naïve B-Cell
115
What components are expressed by a Pro B-cell?
None
Pro B-cells do not express heavy chains, light chains, or surface antibodies
116
What components are expressed by a Pre B-Cell?
* Mu heavy chain in **cytoplasm** (not as a surface receptor)
* No rearranged light chain
117
What components are expressed by an immature B-cell?
* Mu heavy chain and light chain = a fully formed IgM BCR
118
What components are expressed by a Naïve B-cell?
IgM and IgD
(Both sets of antibodies on an individual B-cell have the same antigen binding specificity)
119
What must happen in the transition from pro B-cell to pre B-cell?
Successful rearrangement of the Ig Mu heavy chain
120
What must happen in the transition from pre B-Cell to immature B-cell?
Successful rearrangement of the light-chain (kappa or lambda)
Together, the light chain and heavy chain combine to express IgM in the BCR
121
What must happen in the transition from immature B-cell to Naïve B-cell?
Clonal deletion
* Immature B-cells with IgM that **does not bind** to self-antigen begin expressing IgD with the same light chain specificity as IgM, and they are released from the bone marrow
* Immature B-cells with IgM that **does bind** to self-antigen have two fates...
* 1) undergo apoptosis
* 2) undergo receptor editing; VDJ recombinase is re-expressed via activation of Rag1/Rag2. VJ recombination is repeated to express a second type of **light chain,** which combines with the original heavy chain. If this second type of receptor **does not bind to self** it begins expressing IgD and is released from the bone marrow
122
Which part of IgM is altered in receptor editing?
The light chain variable region
123
Why is B cell clonal deletion and receptor editing important?
* Clonal deletion is necessary to promote the apoptosis of immature B-cells with IgM that binds to self-antigen
* This is important in preventing B-cells from initiating an autoimmune response
* Receptor editing rearranges the light chain of a self-reactive IgM to basically give it a "second chance" to not bind to self-antigen
* If successful, the immature B-cell will begin expressing IgD and continue maturation
124
What is the major cytokine produced by APCs that drives a TH1 CD4+ T cell response?
IL-12
125
What do TH2 CD4+ T helper cells produce?
IL-4, IL-5, and IL-13
126
Where do mycobacteria survive inside cells?
How?
Mycobacteria survive within a phagosome by preventing fusion with the lysosome and acidification
(infection is controlled by a cell-mediated immune response but not always eradicated)
127
What is the classic example of cell-mediated immunity that leads to persistent inflammation?
Granulomatous response to M. tuberculosis
128
Describe the steps involved in granuloma formation due to Mycobacterium tuberculosis infection
1. Chronic antigen stimulation of the organism drives CD4+ TH1 T cell responses (production of IL-2 and IFN-gamma)
2. IFN-gamma drives macrophages to secrete IL-12 and the cycle of activation continues
3. Macrophages secrete hydrolytic enzymes and form granulomas which often have central necrosis
4. These pathways lead to tissue damage but can keep the organism dormant
129
Which viruses can suppress cell-mediated immunity?
Measles and CMV
130
What can suppression of cell-mediated immunity by measles and CMV lead to?
Reactivation of M. tuberculosis infection
131
Infection with which bacterium clearly demonstrates the TH1 versus TH2 response?
Mycobacterium leprae (cause of leprosy)
Th1 - tuberculoid leprosy, intense cell-mediated response, non caseating granulomas, few bacteria
Th2 - lepromatous leprosy, no cellular immune response, many bacteria
132
What response to mycobacteria would you expect in a patient with IFN-gamma receptor deficiency?
Disseminated mycobacterial infection
(need IFN-gamma for granuloma formation)
(latent mycobacterial infection requires intact cell-mediated immunity)
133
What occurs in IL-12 receptor deficiency?
* Decreased TH1 response
* Disseminated mycobacterial infections
* Decreased IFN-gamma
134
How can cross-presentaiton by APCs impact the response to immunization?
Cross-presentation is when APCs, particularly dendritic cells, can present extracellular antigens on the MHC class I molecules to initiate a CD8+ T cell response
Cross-presentation involves a transfer of extracellular antigens from the endosomes into the cytosol of the APC
This can impact immunization design because an antigen that is extracellular (i.e. cannot infect the cell) can still elicit a CD8+ T cell memory response through cross-presentation after uptake by APCs
135
What processes are mediated by activation-induced cytidine deaminase?
Somatic hypermutation
Isotype/class switching
136
Which antibodies can fix complement?
Which pathway do they use?
IgM and IgG fix complement via the classic pathway
137
What are the functions of IgG?
* Fixes complement; activates the classic pathway
* Opsonizes bacteria
* The most effective opsonizer!
* Neutralizes bacterial toxins and viruses
* Most abundant antibody in the secondary immune response
* Can cross the placenta
* Most abundant circulating antibody
* Most effective antibody in many infections
138
Which antibody is most abundant in a primary immune response?
IgM
139
Which antibody is most abundant in a secondary immune response?
IgG
140
Describe the process of ADCC against parasites
ADCC = antibody-dependent cellular cytotoxicity
* IgE binds to the helminth
* An eosinophil recognizes the Fc region of IgE
* The Fc(e)RI receptor on the eosinophil binds the Fc region of IgE
* The eosinophil releases mediators to destroy the helminth
* This is enhanced by IL-5 released by Th2 CD4+ helper T-cells
141
A patient has high baseline levels of IgM and low levels of all other antibodies. Their medical history includes recurrent, severe, pyogenic infections
What is this condition called?
What causes it?
Hyper IgM syndrome
Caused by loss of CD40L on CD4+ helper T-cells
* The B-cells cannot class switch because a germinal center can't form
* The result is high IgM, but low levels of all other Igs
142
What are the 4 major effector mechanisms of antibodies?
1. Neutralize toxins
2. Opsonization
* Via complement deposition (classic) by **IgM, IgG**
* Via exposure of **IgG** Fc (Binds Fc receptors on phagocytes)
3. Antibody-dependent cellular cytotoxicity (ADCC), **IgE**
4. Activates complement cascade; **IgG and IgM**
143
When in life does SCID present?
How can it be treated?
SCID = severe combined immunodeficiency
Presents very early in life: the patient has very low levels of all immunoglobulins, putting them at extremely high risk of life-threatening infection
Permanent treatment = bone marrow transplant
Temporary treatment = give immunoglobulins intravenously
144
What is CVID?
How does it affect patients?
CVID = common variable immunodeficiency
* Caused by multiple etiologies; a variety of different genes may cause an **underlying defect in B cells or helper T-cells**.
* Low immunoglobulins (IgG and IgA, maybe IgM)
* Decreased numbers of memory B-cells
* Impaired humoral immunity
* Increased risk of bacterial, enteroviral, giardial infections
* Presents in late childhood/adolescence
* Increased risk of autoimmune disease an lymphoma
145
What kinds of pathogens does the humoral immune response typically respond to?
Extracellular pathogens
146
What does elevated IgM indicate?
How is this indication different for elevated IgG?
Elevated immunoglobulins indicate exposure to an immunogen
* Elevated IgM = recent exposure to a new virus
* IgM is produced in the early primary response
* Elevated IgG = past exposure
* The individual has immunity to this immunogen
* Produced in later primary response or secondary response
147
How are B-cells co-stimulated?
What happens if there is no co-stimulation?
B-cell co-stimulation
* Cd3 on antigen binds CR2 (aka CD21) on B-cell
* -\> Enhancement of B-cell activation
* PAMP on antigen binds TLR on B-cell
* -\> Enhancement of activaton
If there is no co-stimulation...
* It is likely that the BCR has bound a self-antigen
* Self molecules don't have complement depositions or PAMPs
* To prevent an autoimmune response, the B-cell becomes anergic
149
What is an ITAM?
What processes is it involed in?
ITAM = Immunoreceptor Tyrosine-based Activating Motif
Transmits signal from TCR to the rest of the cell
* When the TCR recognizes antigen in the context of MHC, ITAMS are phosphorylated
* Recrutment and activation of ZAP70 tyrosine kinase
* Signaling cascade
* Increased expression of cytokines, cytokine receptors, cell proliferation genes
* T-cell immune response activation
* **Note: costimulatory signal is required for T-cell activaiton**
150
Which lymphocytes become more specific with repeat exposure to the same antigen?
B-cells
Only B-cells undergo somatic hypermutation to increase their antigen specificity
NK cells do not have antigen specificity, and T-cells do not alter their specificity after leaving the thymus
151
What is peripheral tolerance?
Why is it important?
Peripheral tolerance = the "check" to prevent B-cells and T-cells from reacting to self-antigen after they have completed maturation
* If a BCR or TCR binds to self-antigen, there will be no co-stimulatory signal (at least there shouldn't be)
* B-cell: TLR will not be activated, nor will Cd3 bind to CR2
* T-cell: B7 will not bind to CD28 on the T-Cell, nor will appropriate cytokines activate receptors on the T-Cell
* BCR or TCR binding without a co-stimulatory signal will make the lymphocyte **anergic (nonresponsive to that antigen)**
* T-cells
* Anergy is antigen-specific, but **clonal deletion** will occur if a T-cell repeatedly encounters and reacts to self-antigen
152
What is the function of IFN-gamma?
Which cells secrete it?
* Drives AND is secreted by Th1 CD4+ helper T-cells
* Positive feedback loop
* Promotes and activates macrophages
* Stimulates IgG production
* Leads to more effective killing of **intracellular** pathogens
153
What cytokines do Th1 CD4+ helper T-cells secrete?
* IFN-gamma
* Promotes and activates macrophages
* Stimulates IgG production
* Leads to more effective killing of intracellular pathogens
* Continues to drive the Th1 response
* IL-2
* Promotes T-cell growth and differentiation
* Can act in an autocrine fashion
154
What are the major functions of Th2 CD4+ helper T-cells?
* Fight **extracellular** pathogens
* Support humoral immunity
* Secrete cytokines in the context of CD40:CD40L that promote the formation of a germinal center
* Class switching and affinity maturation of B-cells
155
What proteins do regulatory T-cells (TRegs) express?
Surface
* CD4+, CD25+
Inside of cell
* FoxP3: Regulates gene transcription
* CTLA-4: Binds B7 on APCs
* This prevents B7:CD28 costimulatory interaction needed to activate T-cell
* PD
156
Which cytokines are secreted by TRegs?
IL-10
TGF-beta
157
What mechanisms can cause a hypersensitivity reaction against self-antigen?
1. A foreign molecule cross-links or modifies a host cell
* The host cell recognizes these "new" epitopes as foreign and mounts an immune response
2. Molecular mimicry
* An antibody specific for a foreign antigen binds to similar-lookig self-antigens inside fo the host
158
What challenges does the GI tract immune system face?
* Tolerance of food antigens
* Tolerance of commensal microbiota
* \>500 types
* Outnumber human cells in the whole body
* Must repond to pathogens that are relatively rare
* Large surface area
159
What specialized cells play a role in the GI tract immune system?
What are their functions?
* M cells
* Luminal antigen sampling
* Secretory IgA, IgM
* Neutralized microbes in the lumen
* Dendritic cell subsets
* Luminal and lamina propria antigen sampling
* T-cell tolerance induction
* Effector T-cell activation
* Induction of B-cell IgA class switching
* Imprint gut-homing phenotypes of B cells and T cells
160
Describe the components and function of the mucus layer of the GI tract immune system
Part of the **innate** immune response
* Mucus is produced by goblet cells
* It contains...
* Glycocalyx
* Mucins + glycolypids
* A dense layer that prevents pathogens from contacting the intestinal epithelium
* Defensins
* Defend against luminal bacteria
* Kills microbes by disrupting their glycolipid membrane
161
What are some of the specialized components of the respiratory immune system?
* Tonsils
* Adenoids
* Ciliated respiratory epithelial cells (respiratory elevator)
* Secretory IgA, IgM, IgG
162
Describe the respiratory epithelium as it relates to the respiratory regional immune system
**Innate**
* Physical barrier
* Pseudostratified, ciliated, columnar epithelium
* Chemical barrier
* Mucins, defensins, cathelicidins trap foreign substances
* Surfactant
* In alveoli
* Prevents spread of infection
* Suppresses inflammatory allergic response in the lungs
* MALT
* Alveolar macrophages
* Anti-inflammatory
* Inhibit T-cell response
**Adaptive**
* Mast cells, eosinophils, dendritic cells, CD4+ helper T-cells
* IgA - mosty in upper airway
* IgE - mediates allergic response, asthma when bound to mast cells
163
What are some of the specialized components of the cutaneous immune system?
Keratinocytes
Langerhans cells
Dendritic cells
164
A patient presents with chronic, episodic symptoms of rash, myalgias, diarrhea and bloating following eating, and fatigue
They report that this has been happening for years, but the episodes aren't worsening over time.
**What condition do you think this patient has?**
**What findings would support your diagnosis?**
Celiac disease
Confirm with colonoscopy of small bowel mucosa
* Look for atrophy (blunting) of intestinal villi following an episode
165
What is the mechanism underlying Celiac disease?
* CD4+ helper T-cells respond to gliadin (a component of gluten
* The body forms IgA, IgG, specific for gluten and transglutaminase 2A
* This leads to chronic inflammation
* Atrophy of the intestinal villi
* Malabsorption
* Nutritional deficiency
* Extra-intestinal manifestation
* Rash
* Myalgia
* Diarrhea/bloating
* Fatigue
166
What is the mechanism underlying food allergy?
Failure of the adaptive immune system to tolerate food antigen
* Too many Th2 CD4+ helper T-cells, not enough TRegs
* Overactive Th2-dependent IgE response to antigen
* Mast cells are activated
* Potent mediators/cytokines are released
* Acute inflammatory reactions (including systemic anaphylaxis)
167
What is the mechanism underlying MALT lymphoma?
* H. pylori infection leads to an inflammatory reaction
* Malignant transformation of B-cells in the lymphoid follicles in the gastric lamina propria
* Gets progressively worse over time (without treatment)
168
A 27 yo male comes to urgent care complaining of 3 days of diarrhea. It started out watery, now has some streaks of blood. He's also had moderate abdominal pain with urgency, worse after eating. On exam he is quite thin, and says he has been eating less during these diarrhea episodes which occur every 2-3 months for the last year
## Footnote
**What is your diagnosis?**
IBD (Crohn's disease)
Long lasting = probably not allergies
Episodic = not MALT lymphoma
169
What is the mechanism underlying IBD?
* Polymorphisms of genes associated with bacterial processing, sensing, and autophagy
* Defective TReg function
170
A 42 yo M comes to urgent care c/o diarrhea x4 days. He has also had intermittent lower abdominal pain and a low grade temp (100.1). Stool is mostly watery, but a couple episodes were had a bit of mucus and possibly a streak of blood this morning. With further history, he notes he just finished a 14 day course of antibiotics (Clindamycin) 3 days ago for a difficult to treat sinus infection.
## Footnote
**What is your diagnosis?**
Clostridium difficile (C. diff) colitis
Acute = not IBD or celiac
Fever = infection
Also supported by associated antibiotic use
171
A 32 yo F comes to clinic for f/u. She reports about 3 weeks of increasing difficulty breathing through her nose. She also c/o b/l sinus pressure and a worsening sense of smell. She denies any fever, last used antibiotics for a sinus infection 4 months ago. She reports having surgery in her sinuses about 5 years ago when things used to be this bad, but did not bring records.
## Footnote
**What is your diagnosis?**
Chronic rhinosinusitis
No fever = not a sinus infection
Presentation in the nasal/respiratory airway and mucosa
172
What is the underlying mechanism of psoriasis?
Dysregulated innate and T-cell mediated immune responses
* Overactive plasmacytoid dendritic cells
* Respond to environmental stimuli
* Produce IFN-alpha
* T-cells circulate to the dermis
* Overactive Th1, Th17 cells
* Secrete too much IL-17
* Persistent keratinocyte proliferation
173
A 2 yo M comes to clinic for f/u. His mother notes he has trouble sleeping at night because he is "always scratching." His exam shows globally dry skin, with patches of redness and hyperpigmentation in his antecubital fossa and popliteal fossa
## Footnote
**What is your diagnosis?**
Eczema
Very itchy, dry skin, patches of redness and hyperpigmentation
174
List the immune-privileged tissues in the body
Brain
Eye
Testes
175
A 2-year old patient with a history of recurrent viral and pneumocystis jiroveci fungal infections (6 total in the last 6 months) presents with Q-fever.
Do you suspect an immune deficiency? Why?
If so, which cells are deficient?
**Yes, you should suspect an immune disorder**
* *P**neumocystis jiroveci* is not usually seen in patients with super healthy immune systems
* It is an opportunistic fungus
* Also commonly seen in HIV patients
Infection with viruses, fungi, and coxiella brunetti (cause of Q fever, obligate intracellular) point to a **T-cell deficiency**
* SCID
* DiGeorge syndrome
176
What are the clinical manifestations of chronic granulomatous disease (CGD)?
**Individuals with CGD don't have enough NADPH oxidase to kill via respiratory burst**
* They cannot create O2-, which is needed to make H2O2, and subsequently the hypochlorite ion
* They must kill organisms using the oxygen-independent pathway
**You would expect a patient to experience...**
* Recurrent infections from catalase positive organisms
* Catalase interferes with the oxygen-independent pathway of killing
* Granuloma formation (lungs, liver, brain)
* Severe infections of skin and bone
* Recurrent oral stomatitis
* Infections of respiratory tract and skin
* Abscess formation
177
Which immune deficiency is characterized by recurrent infections from catalase-positive organisms, granuloma formation, and abscess formation?
Chronic granulomatous disease (CGD)
178
Which primary immune deficiency is characterized by recurrent bacterial infections without appropriate pus formation?
Leukocyte adhesion deficiency (LAD)
Neutrophils cannot reach their destinations at the site of infection
179
Which cells are deficient in Chediak-Higashi syndrome?
What are the clinical manifestations?
Phagolysosomes do not form; there is a defect in phagosome-lysosome fusion
NK cells are also abnormal
**Clinical manifestation**
* Impaired killing of intracellular pathogens = recurrent **pyogenic infections**
* Bacterial and viral
* Other abnormalities
* Partial albinism
* Abnormal platelet function
* Defective NK cells
180
Describe the clinical manifestations of a complement defect
Defects in C2 and C4
* Autoimmune disease
* Ex: Systemic lupus erythematosus
Defects in C2 and C3
* Infections by encapsulated bacteria
Defects in any of C5b-C9
* Recurrent, invasive nesseria infections
181
List the 4 major genetic defects that can lead to SCID
Describe each one briefly
SCID = severe combined immunodeficiency
* Mutation in the x-linked gene encoding the **common gamma chain**, an important component of many IL receptors
* Lack of IL-7, IL-15 signaling = defective T and NK cells
* A mutation in **RAG1/RAG2 that prevents VDJ recombination**
* No B or T cells
* **Loss of MHC II** due to loss of transcription factors required for expression leads to **bare lymphocyte syndrome**
* No T cell positive selection = **no T-cells**
* Impaired CD4+ T cell activation
* Defective cell-mediated immunity
* Defective T-cell dependent humoral immunity
* **Defective T cell signaling** due to defective TCR/CD3 complex component or T cell activation signal transduction cascade
* Decreased T cells
* Abnormal CD4+ : CD8+ ratio
* Defective cell-mediated immunity
182
Which PIDs are associated with **pyogenic** infections?
Which are associated with **failure to form pus**?
**Pyogenic (pus-forming) infections**
* B-cell abnormalities
* Chediak-Higashi syndrome (innate)
* Defect in TLRs (innate)
**Failure to form pus**
* Leukocyte adhesion defect (LAD)
183
What are the clinical presentations and consequences of Wiskott-Aldrich syndrome?
Histology
* Abnormal platelets and leukocytes
* Small
* Do not migrate normally
Disease
* Eczema
* Thrombocytopenia
184
What causes Hyper IgE syndrome?
A mutation in STAT3 that results in abnormal Th17 CD4+ helper T cell development. aka Job's syndrome.
185
What is the recommended treatment for SCID?
Bone marrow transplant
Gene therapy (in development)
