Flashcards
(271 cards)
1
Q
What are the main aims of studying immune system cells?
A
To understand different immune cells, recognize their characteristics, and explain how to distinguish between them.
2
Q
What are the main types of cells involved in immunity?
A
All white blood cells (leukocytes) and some other cells, including endothelial cells, adipocytes, and epithelial cells.
3
Q
Where do immune cells originate from?
A
They originate from self-renewing stem cells in the bone marrow, which differentiate into pluripotent stem cells and then into progenitor cells.
4
Q
What are the two main progenitor cell lineages for leukocytes?
A
Myeloid lineage and lymphoid lineage.
5
Q
What is the function of the ‘CD’ system (Cluster of Differentiation)?
A
It is a standardized system to identify immune cells based on specific molecules they express, established in 1982.
6
Q
What does the myeloid progenitor cell give rise to?
A
Polymorphonuclear cells (PMNs), monocytes, megakaryocytes, mast cells, and erythrocytes.
7
Q
What are polymorphonuclear cells (PMNs)?
A
Granulocytes, including neutrophils, eosinophils, and basophils, which make up 60-70% of white blood cells.
8
Q
What are the functions of neutrophils?
A
They are highly phagocytic, kill bacteria using microbicidal mechanisms, release neutrophil extracellular traps (NETs), and play a crucial role in non-viral infections.- 90% of granulocytes are neutrophils
9
Q
What is a defining characteristic of eosinophils?
A
They contain prominent granules with Major Basic Protein (MBP), which is cytotoxic to parasites and important in immunity against helminth (worm) infections.
10
Q
What role do basophils play in the immune system?
A
They promote inflammation, play a key role in allergic reactions, and have receptors for antibodies but do not phagocytose.
11
Q
Where do mast cells mature, and what is their function?
A
They pass through the blood as immature cells and mature in connective and mucosal tissues, where they release mediators like histamine to trigger allergic responses.
12
Q
What is the difference between monocytes and macrophages?
A
Monocytes circulate in the blood for 1-2 days, while macrophages reside in tissues, grow larger, live longer, and have enhanced phagocytic capabilities.
13
Q
What are some specialized types of macrophages based on tissue location?
A
- Kupffer cells – Liver
- Histiocytes – Connective tissue
- Alveolar macrophages – Lungs
- Microglial cells – Brain
- Osteoclasts – Bone
- Mesangial cells – Kidney
14
Q
What are dendritic cells, and what is their primary role?
A
Dendritic cells are irregularly shaped immune cells found in most tissues; they capture antigens and migrate to lymphoid tissues to present them to T cells.
15
Q
What are megakaryocytes, and what is their function?
A
Megakaryocytes are large bone marrow cells that fragment into platelets, which play a crucial role in blood clotting.
16
Q
What percentage of white blood cells are lymphocytes?
A
20-30% of peripheral blood white cells.
17
Q
What happens to lymphocytes when stimulated by an antigen?
A
They become either effector cells or memory cells.
18
Q
What are the two main types of lymphocytes?
A
T cells and B cells.
19
Q
Where do B lymphocytes develop, and what is their role?
A
They develop in the bone marrow, express antibodies as B cell receptors (BCRs), and differentiate into plasma cells to secrete antibodies or into memory B cells.
20
Q
What markers do B cells express?
A
CD19 and CD20.
21
Q
Where do T lymphocytes mature, and what is their function?
A
They mature in the thymus, where they develop T cell receptors (TCRs) to recognize foreign peptides and differentiate into various T cell subsets.
22
Q
What is the difference between CD4+ and CD8+ T cells?
A
- CD4+ (Helper T cells) – Secrete cytokines to assist immune responses.
- CD8+ (Cytotoxic T cells) – Kill infected cells using perforins and granzymes.
23
Q
What are the four subtypes of helper T cells?
A
- TH1 – Cellular immunity
- TH2 – Humoral (antibody-mediated) immunity
- TH17 – Inflammation and autoimmune responses
- TReg (Regulatory T cells) – Suppress immune responses
24
Q
What are gamma-delta (γ/δ) T cells, and where are they found?
A
They have γ/δ chains in their TCRs instead of α/β, are abundant in mucosal tissues, and recognize lipid antigens.
25
What are innate lymphoid cells (ILCs)?
They are lymphocyte-like cells that bridge innate and adaptive immunity and secrete cytokines to regulate immune responses.
26
What are the two main groups of large granular lymphocytes?
Natural Killer T cells (NKT) and Natural Killer (NK) cells.
27
What are Natural Killer (NK) cells, and what do they target?
NK cells kill tumor cells and virus-infected cells by recognizing self and non-self molecules using specialized receptors.
28
What is the key difference between NK cells and NKT cells?
- NK cells – No TCR but have various activating and inhibitory receptors.
* NKT cells – Have TCR and CD3 but lack CD4 and CD8.
29
How do NK cells kill their targets?
By releasing cytotoxic granules containing perforins and granzymes or by inducing apoptosis.
30
How do immune cells recognize ‘foreign’ material?
Through surface receptors, phagocytosis, antigen presentation, and CD markers.
31
What are the three primary roles of immune cells?
1. Phagocytosis (e.g., neutrophils, monocytes, macrophages, dendritic cells).
2. Cytotoxic activity (e.g., CD8+ T cells, NK cells, NKT cells).
3. Secretion of immune mediators (e.g., B cells producing antibodies, helper T cells producing cytokines)
32
What is the main aim of studying immune system tissues?
To understand the structure and function of primary and secondary lymphoid organs/tissues.
33
What are the learning outcomes of this topic?
1. Identify and describe the structure of primary and secondary lymphoid tissues.
2. Explain the processes that develop naïve B and T cells in primary lymphoid tissue.
3. Describe how secondary lymphoid tissues promote a healthy immune response.
4. Discuss how lymphocytes circulate the body.
34
Where are most lymphocytes found in the body?
Although some are found in the blood, most are in organized tissues or discrete clusters.
35
What are the three categories of immune tissues?
1. Primary lymphoid tissues – Where lymphocytes develop and mature.
2. Secondary lymphoid tissues – Where antigen accumulation and immune responses occur.
3. Tertiary lymphoid tissues – Other lymphoid sites, typically containing few lymphocytes unless inflamed.
36
What are the primary lymphoid tissues, and what are their functions?
* Thymus – T cell maturation and education.
* Bursa equivalent tissues (Bone Marrow & Fetal Liver) – B cell development in humans.
37
What is the function of the thymus?
It produces and educates T lymphocytes, ensuring they recognize self and non-self molecules appropriately.
38
How does the thymus change with age?
It involutes (shrinks), reducing its ability to produce new T cells over time.
39
What are the structural components of the thymus?
* Two lobes divided into lobules by trabeculae (connective tissue walls).
* Each lobule has an outer cortex and an inner medulla.
40
What types of cells are present in the thymus?
* Thymocytes (immature T cells).
* Epithelial cells.
* Interdigitating dendritic cells.
* Macrophages.
41
How do thymocytes develop into mature T cells?
1. Enter the thymus as double-negative (CD4- CD8-) cells.
2. Express both markers (double-positive CD4+ CD8+).
3. Final differentiation into either CD4+ helper T cells or CD8+ cytotoxic T cells.
42
What is positive and negative selection in T cell maturation?
* Positive selection – Ensures T cells can bind MHC molecules.
* Negative selection – Eliminates T cells that strongly bind self-peptides to prevent autoimmunity.
43
What percentage of thymocytes successfully mature into naïve T cells?
Only a small percentage survive selection and enter circulation as naïve T cells.
44
How do B cells mature in the bone marrow?
* Immature B cells rearrange their B cell receptors (BCRs).
* Undergo negative selection (eliminating self-reactive B cells).
* Receive survival signals (positive selection).
* Mature B cells leave the bone marrow as naïve B cells.
45
What is the function of the lymphatic system?
* Drains extracellular fluid from tissues into lymphatic vessels.
* Allows lymphocytes and immune cells to migrate throughout the body.
46
How do lymphocytes migrate in the body?
* They circulate between tissues, lymphoid organs, and blood.
* Movement is regulated by adhesion molecules and chemotactic signals.
47
What prevents backflow in the lymphatic system?
* Valves in lymphatic vessels.
* Smooth muscle contractions.
* Arterial pressure from nearby blood vessels.
48
What is lymphocyte homing?
* It is the directed movement of lymphocytes to specific tissues.
* Adhesion molecules (e.g., LFA-1 on lymphocytes) bind to receptors (e.g., ICAM-1 on endothelial cells).
49
What are the main secondary lymphoid tissues?
1. Lymph nodes.
2. Spleen.
3. Mucosa-associated lymphoid tissue (MALT).
50
What is the structure of a lymph node?
* Capsule enclosing the node.
* Cortex (outer layer, contains B cell follicles).
* Paracortical area (T cells and antigen-presenting cells).
* Medulla (plasma cells secreting antibodies).
51
How do lymphocytes enter and exit lymph nodes?
* Enter via high endothelial venules (HEV) or afferent lymphatics.
* Exit via efferent lymphatic vessels, eventually draining into blood circulation.
52
What happens in the lymph node after antigen exposure?
* Germinal centers form in B cell follicles.
* B cells proliferate and differentiate into plasma or memory cells.
53
What are the two main tissue types in the spleen?
* Red pulp – Filters old/damaged red blood cells.
* White pulp – Generates immune responses like a lymph node.
54
What is the Periarteriolar Lymphatic Sheath (PALS)?
A T cell-rich area surrounding arterial branches in the spleen, involved in antigen recognition.
55
What is MALT?
A collection of diffuse lymphoid tissues in the mucosal linings of the respiratory, gastrointestinal, and urogenital tracts.
56
What are GALT and BALT?
1. GALT (Gut-Associated Lymphoid Tissue) – Includes Peyer’s patches in the intestines.
2. BALT (Bronchus-Associated Lymphoid Tissue) – Found in respiratory tract.
57
How do antigens enter Peyer’s patches in GALT?
Through M cells that transport antigens to immune cells in lymphoid follicles.
58
What is inducible BALT (iBALT)?
A temporary accumulation of lymphoid cells in the lungs after infection, helping in immune responses.
59
What are the main functions of primary and secondary lymphoid tissues?
* Primary tissues educate and develop lymphocytes (Thymus, Bone Marrow).
* Secondary tissues facilitate immune responses by accumulating antigens and immune cells (Lymph Nodes, Spleen, MALT).
60
What are eosinophils, and where are they commonly found?
Eosinophils are granulocytes making up about 0.5–1% of white blood cells in healthy individuals. They often increase (3–5% or higher) in allergic conditions or parasitic infections and commonly reside in tissues, especially at mucosal surfaces.
61
What is the primary role of eosinophils in host defense?
Eosinophils are major effector cells against parasitic infections (e.g., nematodes). They contain toxic granule proteins (MBP, ECP, EDN, EPO) that can kill parasites but also damage host tissues if overactivated.
62
Which cytokines/chemokines are crucial for eosinophil development and recruitment?
IL-5 and CCL11 (eotaxin) drive eosinophil differentiation and maturation in the bone marrow, while CCR3 on eosinophils helps them migrate to inflamed tissues.
63
How do eosinophils contribute to pathology in allergic diseases like asthma?
Eosinophil activation and inappropriate accumulation can exacerbate inflammation in allergic diseases (e.g., allergic asthma) by releasing toxic granules that damage host tissue.
64
Name one strategy to limit eosinophil-mediated tissue damage.
Therapies may block IL-5 or target CCR3 to reduce eosinophil activation and recruitment, thereby limiting tissue injury.
65
How do γδ T cells differ from conventional (αβ) T cells?
They have TCRs composed of γ and δ chains rather than α and β, often respond independently of MHC, and are considered “unconventional” T cells.
66
Where are γδ T cells commonly found, and why are they important there?
They frequently reside in epithelial and mucosal tissues (e.g., skin, gut), acting as a first line of defense through stress surveillance and responding rapidly to tissue damage or infection.
67
What types of antigens do γδ T cells typically recognize?
Many γδ T cells don’t require MHC. They often recognize non-peptide antigens (e.g., phosphoantigens, stress molecules) or CD1-presented lipids.
68
How do γδ T cells participate in immunity beyond direct cytotoxicity?
They produce cytokines (IFN-γ, TNF-α, IL-17), help recruit other immune cells, can bridge innate and adaptive immunity, and sometimes serve as antigen-presenting cells.
69
Why are γδ T cells considered a promising avenue in cancer immunotherapy?
γδ T cells can kill tumor cells in an MHC-unrestricted manner, offering a pan-population approach to immunotherapy with potentially broader coverage than conventional αβ T-cell therapies.
70
What defines a T lymphocyte as “helper” vs. “cytotoxic”?
Helper (CD4+) T cells assist other immune cells (B cells, macrophages), while Cytotoxic (CD8+) T cells directly kill virally infected or tumor cells. Their co-receptor (CD4 or CD8) distinguishes them.
71
How do helper T cells recognize antigens, and which MHC do they require?
Helper T cells’ TCRs see peptide antigens presented on MHC class II on antigen-presenting cells (e.g., dendritic cells). The CD4 co-receptor stabilizes this interaction.
72
How do cytotoxic T cells recognize and eliminate target cells?
Cytotoxic T cells recognize peptides on MHC class I from infected or malignant cells; they kill targets using perforin and granzymes, which induce apoptosis.
73
What is the role of the CD3 complex in T cells?
CD3 is a set of signaling chains associated with the TCR, crucial for transducing the antigen-binding signal inside the T cell, enabling activation.
74
Which T-cell subset is typically associated with “double negative” expression (lacking CD4 and CD8)?
Some specialized T cells (e.g., certain γδ T cells, NKT cells) can be CD4–CD8– (“double negative”).
75
How do macrophages arise, and what is their primary function?
Blood monocytes leave circulation and differentiate into macrophages in tissues. They are specialized for phagocytosis, pathogen killing, and initiating inflammation by cytokine release.
76
Can you name distinct tissue-resident macrophage types and their locations?
Examples include Kupffer cells (liver), Alveolar macrophages (lung), Microglia (CNS), and Splenic macrophages (spleen).
77
Which pattern recognition receptors do macrophages often use to detect pathogens?
They commonly use Toll-like receptors (TLRs) to recognize PAMPs (Pathogen-Associated Molecular Patterns) like LPS, flagellin, or microbial nucleic acids.
78
Beyond phagocytosis, how else do macrophages influence immune responses?
Macrophages secrete cytokines (e.g. IL-1, IL-6, TNF-α) to activate other immune cells, present antigen to T cells, and produce reactive oxygen species like nitric oxide.
79
What is the significance of macrophage heterogeneity in different tissues?
Each tissue’s macrophages can display specialized forms, shapes, receptors, and inflammatory profiles adapted to the tissue’s unique environment and functions.
80
Why are NK cells classified as part of the innate lymphoid cell family (ILC)?
NK cells respond rapidly to pathogens or tumors without the need for prior sensitization (unlike adaptive T/B cells), placing them in the innate immune system (Group I ILCs).
81
What is the key function of NK cells in immune defense?
NK cells identify and kill virally infected or tumor cells by releasing cytotoxic granules (e.g., perforin, granzymes). They also produce IFN-γ to modulate immune responses.
82
How do NK cells distinguish healthy cells from abnormal cells?
NK cells integrate signals from activating and inhibitory receptors. Healthy cells usually express sufficient MHC I → recognized by inhibitory receptors, preventing kill. Pathologic cells often lack MHC I → triggers NK killing (“missing self” hypothesis).
83
In what way have NK cells been targeted for cancer immunotherapy?
NK cells can kill cancer cells in an MHC-unrestricted manner. Therapies involve stimulating NK activity with cytokines, blocking inhibitory checkpoints, or adoptive transfer of activated NK cells.
84
Aside from killing infected or malignant cells, do NK cells have any other roles?
Yes. NK cells secrete TNF-α and IFN-γ, which can shape the broader immune response by activating macrophages, T cells, and other innate immune components.
85
What distinguishes neutrophils from other white blood cells?
Neutrophils are polymorphonuclear granulocytes with a multi-lobed nucleus and abundant granules containing antimicrobial factors. They are the most abundant WBCs in blood.
86
When and how do neutrophils typically arrive at sites of infection or inflammation?
They are first responders in acute inflammation, guided by chemokines like CXCL8 (IL-8) from injured tissues. They extravasate into tissues and form a large portion of pus.
87
Describe the main antimicrobial mechanisms of neutrophils.
Neutrophils phagocytose pathogens into phagosomes, fuse with granules containing enzymes, and produce reactive oxygen species. They can also release NETs (neutrophil extracellular traps).
88
How do neutrophils contribute to immune regulation beyond direct pathogen killing?
Neutrophils can secrete cytokines/chemokines, influence dendritic cells, T cells, B cells, and sometimes linger longer than expected if survival signals (cytokines) are present.
89
What does NET formation entail, and how does it help control pathogens?
NETs occur when neutrophils extrude their nuclear DNA/enzymes, forming extracellular traps that capture and kill microbes outside the cell.
90
What defines “invariant” NKT (iNKT) cells?
They have a restricted TCR repertoire (e.g., human Vα24-Jα18, Vβ11) that recognizes glycolipid antigens presented by CD1d, rather than conventional MHC.
91
How do iNKT cells help bridge the innate and adaptive immune systems?
iNKT cells quickly release large amounts of cytokines (e.g., IFN-γ, IL-4) upon activation, modulating dendritic cells, NK cells, T/B cells, and shaping the immune response.
92
Why might iNKT cells be considered for immunotherapy?
iNKT cells can rapidly produce immunoregulatory cytokines and show anti-tumor activity (e.g., via α-GalCer activation). Therapies aim to harness their potent anti-cancer or tolerance-inducing effects.
93
What is the prototypical antigen recognized by iNKT cells, and how was it discovered?
α-galactosylceramide (α-GalCer) from a marine-sponge source potently activates iNKT cells and showcases their strong anti-tumor potential.
94
Do iNKT cells only have beneficial effects?
While they can combat infection and tumors, iNKT cells may exacerbate certain pathologies (like allergy) by overproduction of Th2 cytokines.
95
What distinguishes regulatory T cells (Tregs) from other CD4+ T cells?
Tregs classically co-express CD4 and CD25 and require the FoxP3 transcription factor for development and function. They suppress or regulate other immune responses.
96
How do Tregs develop, and what are the two main types?
Tregs can arise naturally in the thymus (“natural” Tregs) or differentiate from naïve T cells in the periphery or in vitro (“adaptive” Tregs).
97
Which immunosuppressive cytokines are often produced by Tregs?
Tregs produce IL-10, TGF-β, and sometimes adenosine, all of which help dampen immune responses and maintain tolerance.
98
What happens if the FoxP3 gene is mutated?
It can result in autoimmune disorders, exemplified by IPEX in humans and scurfy phenotype in mice, indicating FoxP3’s crucial role in Treg function.
99
What are the markers commonly associated with Tregs besides FoxP3?
CD25 (IL-2 receptor α chain), CTLA-4 (CD152), and GITR are frequently expressed, though some are also transiently upregulated on activated non-regulatory T cells.
100
What drove the discovery of Th17 cells beyond the original Th1/Th2 paradigm?
Certain autoimmune diseases and extracellular fungal/bacterial infections couldn’t be explained by just Th1/Th2. Researchers found IL-17–producing CD4+ T cells with distinct function.
101
Which cytokine signature and function define Th17 cells?
Th17 cells primarily secrete IL-17, crucial for neutrophil recruitment and extracellular pathogen defense. Dysregulated Th17 responses can lead to autoimmunity.
102
Which cytokine produced by antigen-presenting cells is key for Th17 cell development?
IL-23 is essential to activate and stabilize Th17 cells. Additional signals like IL-6 and TGF-β can initiate Th17 differentiation.
103
In what autoimmune conditions are Th17 cells implicated?
Th17 cells are associated with rheumatoid arthritis, multiple sclerosis, psoriasis, and other inflammatory diseases involving excessive IL-17 activity.
104
Why are Th17 cells important for protection against extracellular fungi/bacteria?
IL-17 from Th17 cells promotes neutrophil mobilization and defense at mucosal barriers, critical for clearing extracellular pathogens (e.g. Candida).
105
Where do Tfh cells predominantly reside, and what is their main function?
T follicular helper (Tfh) cells localize in B-cell zones (e.g., germinal centers) of secondary lymphoid organs to help B cells produce high-affinity, class-switched antibodies.
106
Which transcription factor and surface markers characterize Tfh cells?
Bcl-6 is the key transcription factor, and Tfh typically express CXCR5, PD-1, and ICOS at high levels, particularly in germinal centers.
107
How do Tfh cells facilitate germinal center reactions and B-cell differentiation?
Tfh provide CD40L–CD40 interactions and produce IL-21 (plus other cytokines), driving B-cell proliferation, affinity maturation, and class switching.
108
What can happen if Tfh cell function is dysregulated?
Excess Tfh activity can contribute to autoantibody production (e.g., in lupus), while Tfh insufficiency can lead to poor antibody responses and immunodeficiency.
109
Why are Tfh cells a focus for vaccine development?
Because long-lasting, high-affinity antibody production (a major goal of vaccination) depends heavily on Tfh-mediated germinal center support for B cells.
110
Where and how do B cells develop before maturing to participate in adaptive immunity?
B cells initially develop in the fetal liver (prenatally) and later in the bone marrow throughout life. They undergo immunoglobulin gene rearrangements (heavy then light chain) and emerge as immature IgM+ B cells.
111
What happens to immature B cells that recognize self-antigens too strongly?
Such B cells are removed or inactivated (e.g., apoptosis, anergy) through negative selection mechanisms in bone marrow (and further in peripheral sites), preventing autoreactive clones from maturing.
112
Once activated by antigen, what are two main pathways B cells can follow?
1. Extrafollicular response → short-lived plasmablasts producing mostly IgM.
2. Germinal center (GC) reaction → undergo affinity maturation (somatic hypermutation) and class-switch recombination, leading to high-affinity memory B cells or long-lived plasma cells.
113
What is the role of 'Regulatory B cells' (Bregs)?
Bregs secrete IL-10 and/or TGF-β to dampen T-cell and other immune responses, thus suppressing autoimmunity and maintaining immune tolerance.
114
Why are B1 cells unique compared to conventional B2 (follicular) B cells?
B1 cells are a distinct subset originating largely from the fetal liver, found in body cavities (peritoneal/pleural). They often produce natural antibodies and can respond to T-independent antigens.
115
Where do mast cells originate, and how do they mature?
Mast cells arise from bone marrow progenitors but circulate as immature forms. They fully mature only after entering tissues, often near surfaces (skin, mucosa) or blood vessels.
116
Which key factor is essential for mast cell development and survival?
Stem cell factor (SCF) binding to c-Kit is crucial for mast cell growth, proliferation, and survival.
117
How are mast cells activated in allergic reactions?
Mast cells display FceRI receptors that bind IgE. Crosslinking of receptor-bound IgE by specific allergen triggers degranulation, releasing mediators like histamine and proteases.
118
Name some consequences of mast cell degranulation.
Degranulation releases histamine, leukotrienes, and cytokines → leads to vasodilation, increased vascular permeability (edema), smooth muscle contraction, and local or systemic inflammatory responses (as in anaphylaxis).
119
Beyond allergies, in what other processes are mast cells involved?
Mast cells help defend against parasitic infections, orchestrate tissue repair, and modulate vascular homeostasis. They can also contribute to chronic inflammation in diseases like asthma.
120
How do basophils compare to mast cells in their functions and location?
Basophils are circulating granulocytes (fewer than 1% of WBCs) that share many functional similarities with tissue-resident mast cells (e.g., histamine release via IgE crosslinking), but they mature fully in bone marrow and stay in blood unless recruited to tissues.
121
What drives basophil differentiation?
Basophil development from myeloid progenitors in bone marrow is primarily driven by IL-3 and the basophil’s IL-3 receptor α (CDw123) expression.
122
Which mediators do basophils store and release upon activation?
Basophils contain histamine, produce leukotriene C4 (LTC4), and secrete IL-4, IL-13, and other inflammatory molecules upon IgE-mediated or alternative activation pathways (C5a, C3a, etc.).
123
What roles do basophils play in immunity against pathogens?
They aid in immune defenses particularly against parasites like filarial worms, releasing cytokines and granule contents that help recruit/activate other immune cells.
124
Why are basophils implicated in allergic disease, and which diseases specifically?
Basophils release histamine and IL-4 upon allergen exposure, contributing to inflammatory and late-phase allergic reactions. Elevated basophil numbers are often found in asthma, rhinitis, and atopic dermatitis.
125
What is the main immunological role of CD4+ T cells?
CD4+ T cells function primarily as 'helper' T cells, orchestrating and regulating the adaptive immune response, including B-cell antibody production and macrophage activation.
126
Which MHC class do CD4+ T cells interact with, and how?
CD4+ T cells recognize peptides presented by MHC class II on antigen-presenting cells (APCs) like dendritic cells, macrophages, and B cells. The CD4 co-receptor binds to the β2 domain of MHC II.
127
Name at least two subsets of CD4+ T cells and their functions.
Th1 cells: produce IFN-γ, help eliminate intracellular pathogens.
Th2 cells: produce IL-4, IL-5, IL-13, orchestrate anti-parasite and allergic responses.
128
How do CD4+ T cells help B cells produce high-affinity antibodies?
Through T follicular helper (Tfh) subset interactions in germinal centers, providing CD40L–CD40 co-stimulation and cytokines (e.g., IL-21) that drive class-switch and affinity maturation.
129
Do CD4+ T cells participate directly in cell killing?
Generally, CD4+ T cells do not typically kill target cells themselves (unlike CD8+ T cells). However, certain subsets (e.g., Th1) can produce cytokines that activate macrophages for intracellular pathogen destruction.
130
What distinguishes CD8+ T cells from CD4+ T cells?
CD8+ (cytotoxic) T cells express CD8 co-receptor and recognize antigenic peptides presented on MHC class I (all nucleated cells), enabling them to directly kill infected or tumor cells.
131
Which mechanisms do cytotoxic T lymphocytes (CTLs) use to kill target cells?
CTLs use:
1. Cytokine secretion (IFN-γ, TNF-α).
2. Cytotoxic granules (perforin and granzymes).
3. Fas–FasL interactions (apoptosis induction).
132
Why is the release of cytotoxic granules by CD8+ T cells highly localized?
CTLs form an immune synapse with the target cell, ensuring focused delivery of perforin and granzymes, minimizing bystander tissue damage.
133
What happens if a CD8+ T cell must kill multiple cells in succession?
CTLs can engage in serial killing, moving from one infected/malignant cell to the next after delivering a lethal hit, if still functional and needed.
134
In what way can CD8+ T-cell responses become harmful?
Excessive or misdirected CTL activity can cause immunopathology, e.g., tissue damage in certain infections or autoimmune conditions.
135
Why are dendritic cells called the 'sentinels' of the immune system?
DCs sample their environment for antigens in peripheral tissues, then migrate to lymphoid organs to initiate adaptive immune responses, thus serving as 'sentinels.'
136
How do immature DCs differ from mature DCs in function?
Immature DCs (iDCs): high antigen uptake, roam tissues, low co-stimulatory molecule expression.
Mature DCs (mDCs): after antigen encounter, migrate to LN, present antigen on MHC with high CD80/CD86 co-stim expression, secrete inflammatory cytokines.
137
In which ways can DCs be generated or expanded in vitro for research or therapy?
They can be cultured from blood or bone marrow precursors using growth factors like GM-CSF, IL-4, and/or Flt3L, producing either myeloid or plasmacytoid-like DC populations.
138
Why are DCs considered the most potent antigen-presenting cells (APCs)?
They effectively process extracellular and intracellular antigens, present them on MHC I/II, and activate naïve T cells. A single DC can stimulate hundreds or thousands of T cells.
139
What is the concept behind using DC-based vaccines, particularly in cancer immunotherapy?
DCs loaded with tumor antigens ex vivo and reintroduced into patients can prime strong anti-tumor T-cell responses, bypassing immunosuppressive tumor environments.
140
What is the fundamental difference between 'lymphoid-resident' and 'migratory' DCs?
Lymphoid-resident DCs develop from blood precursors and remain in secondary lymphoid organs.
Migratory DCs reside in peripheral tissues, capture antigen, then travel to draining LNs.
141
How do intestinal (gut) DCs promote tolerance to commensal bacteria and food antigens?
CD103+ gut DCs secrete retinoic acid and TGF-β, favoring regulatory T cell induction, and imprint gut-homing markers on T cells (CCR9, α4β7 integrin).
142
In the lung mucosa, how might DCs drive allergic or Th2 responses?
Epithelial signals (TSLP, IL-25, IL-33) can condition DCs to stimulate Th2 type responses to allergens, leading to allergic inflammation.
143
What is the concept of 'DC conditioning' by epithelial cells?
Tissue epithelial cells release local signals that shape DC phenotypes (e.g., retinoic acid in gut, TSLP in lung), conferring tissue-specific tolerogenic or immunogenic properties.
144
Why is understanding tissue-specific DC function critical for therapy design?
Tissue DCs hold the key to selective immunoregulation (like tolerance vs. immunity). Manipulating them could enable mucosal vaccines or treat inflammatory diseases (IBD, asthma) by modulating local DC responses.
145
146
How is innate immunity defined, and what are its key characteristics?
Innate immunity is the non-specific first line of defense. It is fast, ready from birth, and triggered by tissue damage (from trauma or infection). It involves a series of cellular and chemical events aimed at limiting damage spread, eliminating microorganisms, and repairing tissue, while still recognizing foreign antigens.
147
What are the four main types of defensive barriers or features in innate immunity?
The four features are:
1. Anatomical barriers
2. Physiological/chemical barriers
3. Phagocytic/endocytic mechanisms
4. Inflammatory responses
148
What constitutes the anatomical barriers of innate immunity?
Anatomical barriers include:
* Skin: Acts as a mechanical barrier with features such as dead cell sloughing, an acidic environment (pH 3–5), and secretion of bacteriocins by commensal microflora.
* Mucosal surfaces: Use mechanisms like cilia propulsion (in the nasal/bronchial areas), mucus entrapment, secretions (urine, saliva, tears, milk), and tight junctions between epithelial cells to prevent pathogen entry.
149
What are the key physiological/chemical barriers in innate immunity?
These barriers include:
* Temperature: Normal body temperature (37°C) and fever can inhibit microbial growth.
* Low pH: The acidity in areas such as the stomach and skin helps retard growth.
* Antimicrobial proteins/peptides (AMPs): Examples include enzymes like lysozyme, proteins like lactoferrin and psoriasin, surfactant proteins, and peptides like defensins and cathelicidins.
150
What is the function of lysozyme in innate immunity?
Lysozyme is an enzyme found in secretions such as tears and saliva that cleaves peptidoglycans in bacterial cell walls, particularly targeting gram-positive bacteria.
151
How does lactoferrin contribute to innate immune defense?
Lactoferrin binds essential nutrients, inhibiting the growth of bacteria and fungi. It also plays a role in activating macrophages.
152
What are defensins and how do they function?
Defensins are positively charged polypeptides that bind to negatively charged microbial structures (like LPS or LTA). They aggregate to form pores in the cytoplasmic membranes, thereby damaging microbes, and also activate the complement system via the classical pathway. They are abundant in neutrophil granules and found on skin and mucosal surfaces.
153
What role do cathelicidins play in the innate immune response?
Cathelicidins are antimicrobial peptides that disrupt microbial membranes, particularly those of bacteria. They are predominantly found on mucosal surfaces, contributing to the immediate defense against pathogens.
154
What is phagocytosis and who is credited with its discovery?
Phagocytosis is the process by which specialized cells ingest, kill, and digest particulate matter (larger than 1 µm). Ilya Metchnikoff first described this process in 1883, establishing the concept of cellular immunology.
155
What are the different mechanisms of endocytosis mentioned in the lecture?
The mechanisms include:
* Pinocytosis (cell drinking): Non-specific uptake of extracellular fluid and molecules.
* Macro-pinocytosis: Involves larger volumes or ‘gulps’ of extracellular fluid.
* Receptor-mediated endocytosis: A specific uptake process that uses receptors and clathrin-coated pits.
* Phagocytosis: A specialized form of endocytosis for ingesting large particulate matter.
156
How do pinocytosis and receptor-mediated endocytosis differ?
* Pinocytosis: Involves non-specific internalization of extracellular fluid and nutrients, often referred to as “cell drinking.”
* Receptor-mediated endocytosis: Involves the specific binding of ligands (such as growth factors or hormones) to receptors, which then cluster and form clathrin-coated pits for internalization.
157
Which cells are primarily responsible for phagocytosis?
Phagocytosis is carried out by specialized phagocytes including:
* Neutrophils
* Monocytes and Macrophages
* Dendritic cells
* Eosinophils (to a lesser extent)
Additional cells like B cells and mast cells can also be involved.
158
What are the stages of phagocytosis?
The stages include:
1. Recognition: The phagocyte identifies the target particle.
2. Ingestion: The particle is engulfed into the cell.
3. Digestion: The engulfed material is broken down by enzymes.
4. Exocytosis/Antigen Presentation: Any indigestible material is expelled and parts may be used for antigen presentation.
159
What is the difference between direct and indirect recognition in phagocytosis?
* Direct recognition: Phagocytes use pattern recognition receptors (PRRs) to bind directly to pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) on microbes.
* Indirect recognition: Involves opsonisation, where pathogens are coated with molecules (such as antibodies or complement components) that enhance phagocyte recognition via their receptors.
160
What are Pattern Recognition Receptors (PRRs) and what are some examples?
PRRs are receptors on innate immune cells that recognize common molecular patterns found on pathogens (PAMPs) or released from damaged cells (DAMPs). Examples include:
* Toll-like receptors (TLRs)
* C-type lectin receptors: (e.g., Mannose receptor, Dectin-1, DC-SIGN)
* Scavenger receptors: (e.g., SR-A, SR-B)
161
What are Toll-like receptors (TLRs) and what role do they play?
TLRs are a family of receptors that detect various PAMPs or DAMPs. They can form homodimers or heterodimers and are either located on the cell surface or intracellularly. Their activation triggers signaling pathways (involving NF-κB or IRF transcription factors) that lead to the production of inflammatory mediators.
162
How do TLRs differ based on their localization and the pathogens they detect?
* Cell surface TLRs: Primarily expressed by immune cells (such as macrophages and dendritic cells) and detect bacterial and fungal components.
* Intracellular TLRs: Located in endocytic vesicles; they detect nucleic acids (DNA or RNA) from viruses, leading to strong type I interferon responses.
163
What other cytoplasmic PRRs are involved in innate immunity, and what are their roles?
Other cytoplasmic PRRs include:
* NOD-like receptors (NLRs): Detect intracellular PAMPs/DAMPs, activate NF-κB, and can trigger autophagy.
* RIG-like receptors: Bind viral double-stranded RNA to initiate antiviral cytokine production.
* AIM2-like receptors (ALRs) and cGAS/STING: Bind DNA from pathogens to produce antiviral and inflammatory cytokines. Some of these can form inflammasomes, leading to the production of IL-1 and IL-18.
164
How does opsonisation enhance the process of phagocytosis?
Opsonisation involves coating a pathogen with molecules such as antibodies, complement components, or lectins. These opsonins bind to specific receptors on phagocytes, which enhances recognition and facilitates the engulfment of the pathogen.
165
Which receptors on phagocytes recognize opsonins?
The key receptors include:
* Antibody (Fc) receptors: Recognize the constant region of antibodies (especially IgG).
* Complement receptors: Such as CR1, CR3, and CR4, which bind complement fragments deposited on the pathogen.
166
What is the role of complement activation in innate immunity?
Complement activation, particularly via the classical pathway (triggered by opsonins like antibodies or CRP), results in the coating of pathogens. This coating further enhances phagocytosis by promoting binding to complement receptors on phagocytes and helps in the overall elimination of the pathogen.
167
What are the five hallmarks of acute inflammation?
The five hallmarks are:
* Rubor (redness)
* Tumor (swelling)
* Calor (heat)
* Dolor (pain)
* Loss of function
168
What roles do cytokines play during the inflammatory response?
Cytokines mediate and regulate inflammation by activating local and systemic responses. Pro-inflammatory cytokines (e.g., IL-1, IL-6, TNF-α) induce fever, increase vascular permeability, and stimulate the acute phase response, while anti-inflammatory cytokines (e.g., IL-10, TGF-β) help downregulate inflammation.
169
Name some key pro-inflammatory cytokines mentioned in this presentation.
Key pro-inflammatory cytokines include Interleukin-1 (IL-1), Interleukin-6 (IL-6), and Tumour Necrosis Factor alpha (TNF-α).
170
What are pro-inflammatory cytokines and their effects?
Pro-inflammatory cytokines (e.g., IL-1, IL-6, TNF-α) induce fever, increase vascular permeability, and stimulate the acute phase response.
171
What are anti-inflammatory cytokines and their function?
Anti-inflammatory cytokines (e.g., IL-10, TGF-β) help downregulate inflammation.
172
Name some key pro-inflammatory cytokines mentioned.
Key pro-inflammatory cytokines include Interleukin-1 (IL-1), Interleukin-6 (IL-6), and Tumour Necrosis Factor alpha (TNF-α).
173
What are chemokines and what function do they serve in inflammation?
Chemokines are small proteins that act as chemoattractants, directing the migration of leukocytes to the site of inflammation.
174
Give examples of chemokines.
Examples of chemokines include IL-8 and MCP-1.
175
How do eicosanoids such as prostaglandins and leukotrienes affect the inflammatory response?
Eicosanoids modulate vascular permeability and leukocyte migration, acting like hormones.
176
Provide an example of an eicosanoid's effect.
For example, PGE2 can act on the hypothalamus to induce fever.
177
What role does histamine play during inflammation?
Histamine increases vascular permeability and causes smooth muscle contraction, facilitating leukocyte migration.
178
What are some systemic effects of inflammation?
Systemic effects include fever, increased production of acute phase proteins by the liver, and mobilization of immune cells.
179
Summarize the interplay between phagocytosis and inflammation in the innate immune response.
Phagocytosis involves the recognition, ingestion, digestion, and removal of pathogens, while inflammation ensures increased blood flow and recruitment of immune cells.
180
What are the four main types of defensive mechanisms in innate immunity?
The four types are:
1. Anatomical
2. Physiological/chemical
3. Phagocytic/endocytic
4. Inflammatory
181
Which inflammatory mediators and enzyme cascades are involved in the innate immune response?
Mediators include prostaglandins, leukotrienes, histamine, cytokines, and chemokines. Additionally, four enzyme cascades are interconnected:
1. Kinin
2. Clotting
3. Fibrinolytic
4. Complement
182
How does the kinin system become activated and what role does it play?
Following tissue injury, Hageman factor (Factor XII) activates pre-kallikrein into kallikrein, which then cleaves kininogen to form bradykinin. Bradykinin increases vascular permeability, causes vasodilation, induces pain, and triggers smooth muscle contraction.
183
Describe the clotting system’s role in inflammation.
Tissue injury activates Factor XII, which leads to the release of thrombin. Thrombin converts soluble fibrinogen into fibrin, forming a clot. Fibrinopeptides released during clot formation increase vascular permeability and promote neutrophil chemotaxis while involving platelets.
184
What is the function of the fibrinolytic system in the inflammatory response?
Triggered by endothelial cell damage and Factor XII activation, the fibrinolytic system produces plasmin—a potent proteolytic enzyme. Plasmin degrades fibrin clots into degradation products that are chemotactic for neutrophils and can activate the classical complement pathway.
185
What are the three pathways of complement activation, and what are their main outcomes?
The three pathways are:
* Classical
* Lectin
* Alternative
They lead to:
1. Opsonisation (marking pathogens for phagocytosis)
2. Regulation of inflammatory and immune responses
3. Cytolysis via formation of the membrane attack complex (MAC)
186
How is the classical complement pathway initiated and amplified?
The classical pathway is triggered when opsonins such as antibodies (IgG/IgM) or CRP bind to target antigens/PAMPs/DAMPs. C1 (C1qr₂s₂) binds to this complex and activates, leading to cleavage of C4 and C2 to form C4b2a (the C3 convertase). This enzyme cleaves many C3 molecules, generating C3a (anaphylatoxin) and C3b, which further forms C5 convertase and ultimately drives MAC formation.
187
What distinguishes the lectin complement pathway from the classical pathway?
The lectin pathway is initiated by Mannose Binding Lectin (MBL) or other lectins binding directly to carbohydrates on bacterial or infected cell walls. This complex then recruits MASPs (MBL-associated serine proteases) to trigger a cascade similar to the classical pathway, leading to C3 activation.
188
Describe how the alternative complement pathway is activated.
The alternative pathway involves the spontaneous cleavage of C3 into C3a and C3b. C3b binds to microbial surfaces via PAMP/DAMP interactions, then associates with Factor B in the presence of Mg²⁺. Factor D cleaves Factor B, forming the C3bBb complex (a C3 convertase) stabilized by Properdin. This complex amplifies C3 cleavage and leads to MAC formation.
189
What additional inflammatory effects do C3a and C5a have?
Beyond aiding in complement amplification, C3a and C5a are anaphylatoxins that stimulate the respiratory burst in neutrophils, trigger mediator release (such as histamine from mast cells), and act as chemoattractants for various immune cells.
190
What is the primary outcome of complement activation in the innate immune response?
The key outcomes include enhanced opsonisation (making pathogens easier to phagocytose), regulation and amplification of inflammatory responses, and direct lysis of target cells through the formation of the membrane attack complex (MAC).
191
Which cells and molecules are part of cell-mediated innate immunity (CMI)?
Although often associated with adaptive responses, cell-mediated innate immunity includes:
* Innate Lymphoid Cells (ILCs), such as Natural Killer (NK) cells
* Natural Killer T (NKT) cells
* γδ T cells
* B1 cells
as well as monocytes/macrophages, neutrophils, eosinophils, basophils, and mast cells.
192
How are Innate Lymphoid Cells (ILCs) categorized and what are their functions?
ILCs are grouped into three main types:
* ILC1 and NK cells: Secrete pro-inflammatory TH1-like cytokines (IFNγ, TNFα) and target intracellular pathogens and tumor cells.
* ILC2: Involved in immunity to worms and wound healing; secrete TH2 cytokines that activate eosinophils.
* ILC3: Contribute to lymphoid tissue development, intestinal health, and immunity to extracellular bacteria and fungi; secrete regulatory cytokines.
193
What are the three mechanisms by which Natural Killer (NK) cells kill target cells?
NK cells kill via:
1. Releasing perforins and granzymes to induce pore formation and trigger apoptosis or necrosis.
2. Expressing Fas ligand to induce apoptosis in target cells.
3. Mediating Antibody-Dependent Cellular Cytotoxicity (ADCC) through CD16 (an Fc receptor), which binds antibodies coating the target.
194
How do Natural Killer T (NKT) cells bridge innate and adaptive immunity?
NKT cells express T-cell receptors (TCRs) but do not recognize peptide antigens on MHC molecules; instead, they recognize lipid antigens presented by CD1. They kill target cells mainly via apoptosis (through Fas-Fas ligand interactions) and secrete cytokines (such as IL-2 and TNFα) that modulate innate immune responses.
195
What are the key functions of eosinophils in innate immunity?
Eosinophils contain granules with cationic proteins, such as major basic protein and peroxidase, which they release onto extracellular pathogens (especially parasitic worms) to damage and kill them.
196
What distinguishes neutrophils in cell-mediated innate responses?
Neutrophils have primary granules (rich in lysosomal enzymes and myeloperoxidase) and secondary granules (containing defensins and lactoferrin). They produce high levels of reactive nitrogen intermediates (RNI) and can undergo NETosis to trap and kill pathogens.
197
What roles do γδ T cells play in innate immunity?
γδ T cells are enriched in mucosal and skin tissues. They recognize bacterial antigens (especially lipid antigens via non-MHC mechanisms), express Toll-like receptors, and can phagocytose, process, and present antigens. They are also capable of killing target cells via perforin/granzyme release.
198
What are B1 cells and how do they contribute to innate immune defenses?
B1 cells are a subset of B cells (often CD5 positive) found mainly in the pleural and peritoneal cavities. They produce low-affinity, natural IgM antibodies against bacterial antigens (especially carbohydrates) without requiring T cell help and are important in fetal and neonatal immunity.
199
How do innate and adaptive immunity interact?
Although often studied separately, innate and adaptive immunity function as a highly interactive, cooperative system. Their combined responses are more effective than either branch operating alone, with innate mechanisms providing early defense and shaping subsequent adaptive responses.
200
What role does thrombin play in the clotting system and how does it contribute to inflammation?
Thrombin, generated after tissue injury via Factor XII activation, converts soluble fibrinogen into insoluble fibrin for clot formation. It also releases fibrinopeptides that increase vascular permeability, enhance neutrophil chemotaxis, and promote platelet activation—all of which contribute to the inflammatory response.
201
What is plasmin, and how does the fibrinolytic system use it to aid inflammation?
Plasmin is a potent proteolytic enzyme produced when the fibrinolytic cascade is triggered (often by endothelial damage). It breaks down fibrin clots into degradation products that not only clear clots from injured tissue but also act as chemotactic signals for neutrophils and can activate the classical complement pathway.
202
How is the membrane attack complex (MAC) formed in the complement system, and what is its outcome?
After amplification of the complement cascade, C5 is cleaved to C5b, which then sequentially recruits C6, C7, C8, and multiple copies of C9. This assembly forms the MAC, which creates pores in the target cell membrane, leading to cytolysis and necrosis of the pathogen.
203
In the alternative complement pathway, what role does Properdin play?
Properdin stabilizes the C3bBb complex (the alternative pathway C3 convertase) on microbial surfaces, thereby enhancing its activity. This stabilization allows for more efficient cleavage of C3, amplifying the complement response and contributing to opsonisation and MAC formation.
204
How do Natural Killer (NK) cells determine whether to kill a target cell?
NK cells balance signals from activating and inhibitory receptors. Under normal conditions, inhibitory receptors engage with self MHC I molecules to prevent killing. When target cells downregulate MHC I or express stress-induced ligands, activating signals—such as engagement through CD16 (an Fc receptor)—prevail, triggering the release of perforins and granzymes to kill the target.
205
What is unique about the antigen recognition of Natural Killer T (NKT) cells?
Unlike conventional T cells, NK T cells recognize lipid antigens presented by CD1 molecules instead of peptide antigens presented by MHC. This allows them to respond rapidly to a different set of antigens during innate immune responses and bridge innate and adaptive immunity.
206
How do innate and adaptive immunity interact to provide a more effective overall immune response?
Although distinct, innate and adaptive immunity work cooperatively. Innate responses (like phagocytosis, complement activation, and cytokine release) provide immediate defense and shape the environment for the adaptive response. In turn, adaptive immunity (with its highly specific responses) further refines and amplifies the immune attack, resulting in a combined response that is more effective than either alone.
207
What is an antigen, and how does it differ from an immunogen?
An antigen is any substance that binds to specific receptors on lymphocytes (BCR or TCR), while an immunogen is a molecule (or group of molecules) that induces an immune response. All immunogens are antigens, but not all antigens are immunogens.
208
Define epitope (antigenic determinant) and explain its role in antigen recognition.
An epitope is the specific part of an antigen that binds to the antigen receptor (BCR or TCR). It is usually composed of a small number of amino acids, carbohydrate, or lipid residues, and it determines the specificity of the immune response.
209
What is a hapten, and why is it significant in immunology?
A hapten is a small molecule that, by itself, cannot elicit an immune response but can act as an epitope when attached to a larger carrier molecule. This concept is important in understanding how small substances may become immunogenic when combined with proteins.
210
What types of molecules can serve as antigens?
Antigens can be proteins, lipids, carbohydrates, or any combination thereof. They may be foreign (from pathogens like bacteria, viruses, fungi, or protozoa) or altered self molecules, and they can be either soluble or particulate.
211
Provide examples of simpler versus complex antigens.
Simpler antigens include small molecules like benzene or ovalbumin and pollen. Complex antigens consist of large proteins or polysaccharides that display multiple antigenic determinants, such as bacterial cell wall components or viral proteins.
212
How can antigens enter the body?
Antigens may enter through breaks in the skin or mucous membranes, direct injection (as with a bite or needle), transplants (organ or skin grafts), or via specialized cells (such as M cells in mucosal surfaces).
213
What are adjuvants, and how do they enhance the immune response?
Adjuvants are substances that increase the immunogenicity of an antigen. They work by prolonging antigen persistence (forming a depot), increasing the effective size of the antigen for uptake by APCs, and activating dendritic cells and macrophages to produce inflammatory cytokines. Examples include Complete Freund’s adjuvant and Alum (aluminium potassium sulphate).
214
How do B cell antigens differ from T cell antigens?
B cells recognize native antigens in their natural three-dimensional structure via the B cell receptor (BCR), whereas T cells recognize short, linear peptide fragments that have been processed and are presented on major histocompatibility complex (MHC) molecules by antigen-presenting cells.
215
What is the primary function of the B cell receptor (BCR)?
The BCR allows B cells to bind native antigens directly in solution or suspension. It is essentially a membrane-bound immunoglobulin that confers antigen specificity to each B cell, enabling the recognition of diverse antigens based on their unique variable regions.
216
How do T cells recognize antigens?
T cells recognize processed peptide antigens. The peptides are generated by antigen processing within antigen-presenting cells and then presented on MHC molecules to T cell receptors (TCRs), which bind to these linear peptide fragments rather than to native antigens.
217
Describe the general structure of an antibody molecule.
An antibody is a Y-shaped molecule consisting of two identical heavy chains and two identical light chains joined by disulfide bonds. It has two main regions: the Fab region, which contains the variable domains responsible for antigen binding, and the Fc region, which mediates effector functions through interactions with Fc receptors and complement proteins.
218
What are the variable (V) and constant (C) regions of an antibody, and what are their roles?
The variable regions (VH for heavy chains and VL for light chains) form the antigen-binding sites, including hypervariable loops known as complementarity-determining regions (CDRs) that determine specificity. The constant regions (CH and CL) provide structural stability and mediate effector functions such as complement activation and binding to Fc receptors.
219
List the five classes of immunoglobulins and briefly describe one key feature of each.
IgM: Typically expressed on naïve B cells; forms pentamers in its secreted form. IgG: The most abundant antibody in serum; critical for opsonisation and complement activation. IgA: Predominantly found in mucosal areas; usually forms dimers and provides local immunity. IgD: Expressed on the surface of B cells; its exact function remains less well defined. IgE: Involved in allergic responses and defense against parasitic infections; binds to mast cells and basophils.
220
What is class-switching in B cells, and why is it important?
Class-switching is a genetic recombination process in B cells that changes the constant region of the antibody heavy chain, allowing a B cell to produce different classes of antibodies (e.g., switching from IgM to IgG, IgA, or IgE) while retaining the same antigen specificity. This enables the immune response to be tailored to different pathogens and sites of infection.
221
How does the structure of the B cell receptor (BCR) differ from that of a secreted antibody?
The BCR is essentially a membrane-bound form of an antibody. While its antigen-binding (variable) regions and overall structure are identical to those of the secreted antibody, the BCR has an additional transmembrane domain and is associated with signaling proteins (Igα and Igβ) that transmit activation signals when the antigen binds.
222
What components make up the B cell receptor (BCR) complex?
The BCR complex consists of the membrane-bound immunoglobulin (mIg) along with two Igα and two Igβ chains (CD79α and CD79β), which contain immunoreceptor tyrosine-based activation motifs (ITAMs) essential for signal transduction upon antigen binding.
223
What is the functional significance of the Fab and Fc regions of antibodies?
The Fab region contains the variable domains that bind to specific antigens, while the Fc region mediates effector functions by interacting with Fc receptors on immune cells and activating the complement system, thereby linking antigen recognition to immune responses.
224
How do antibodies mediate their effector functions?
Antibodies mediate effector functions by: Binding to Fc receptors on phagocytes and natural killer cells to promote phagocytosis and cytotoxicity. Activating the complement system, leading to opsonisation or lysis of pathogens. Neutralizing toxins and preventing pathogen entry into cells.
225
Define affinity and avidity in the context of antibody-antigen interactions.
Affinity refers to the strength of the binding interaction between a single antigen-binding site on an antibody and a single epitope on an antigen. Avidity refers to the overall binding strength when multiple antigen-binding sites interact with multiple epitopes, which can greatly enhance the functional binding strength despite lower individual affinities.
226
How do the hypervariable loops (CDRs) contribute to the diversity of the antibody repertoire?
The hypervariable loops (CDRs) in the variable regions of the heavy and light chains vary in amino acid composition and length, providing immense diversity in antigen-binding sites. This variability allows the immune system to recognize and bind to a vast array of different antigenic structures.
227
How do adjuvants improve the immunogenicity of an antigen in vaccines?
Adjuvants enhance immunogenicity by prolonging the antigen's presence in the body (forming a depot), increasing its uptake by antigen-presenting cells, and stimulating local inflammatory responses that activate dendritic cells and macrophages to secrete cytokines, thereby promoting a stronger adaptive immune response.
228
Summarize the role of antigen receptors in the adaptive immune response.
Antigen receptors (BCRs on B cells and TCRs on T cells) are essential for the recognition of specific antigenic determinants. They enable lymphocytes to identify and bind to their target antigens, triggering clonal expansion and differentiation into effector and memory cells, which are critical for a targeted and long-lasting immune response.
229
Compare and contrast how B cells and T cells recognize antigens.
B cells recognize native antigens in their soluble, three-dimensional form via the B cell receptor (BCR), which binds to conformational epitopes. T cells recognize processed peptide fragments presented by MHC molecules on antigen-presenting cells via the T cell receptor (TCR), binding to linear epitopes. This difference underlies the distinct roles of B and T cells in the adaptive immune response.
230
What is an epitope, and why is it important in antigen–antibody interactions?
An epitope (or antigenic determinant) is the specific, discrete part of an antigen that is recognized and bound by the antigen-binding site (paratope) of an antibody or T cell receptor. Its precise structure (which can be linear or discontinuous) determines the specificity of the immune response.
231
Define the term 'affinity' in the context of immunoglobulin–antigen interactions.
Affinity is the strength of the binding interaction between a single antigen-binding site of an antibody (or B cell receptor) and a single epitope on the antigen. A higher affinity means a stronger, more specific interaction.
232
What does 'avidity' refer to, and how does it differ from affinity?
Avidity is the overall strength of binding between a multivalent antibody (with multiple antigen-binding sites) and a multivalent antigen, reflecting the cumulative binding strength. Unlike affinity (a single interaction), avidity considers the combined effect of all binding sites interacting simultaneously with repeated epitopes.
233
Why might IgM antibodies, despite their low individual affinity, be very effective?
IgM antibodies have low affinity at each binding site but exist as pentamers (or even hexamers) with multiple binding sites, resulting in high avidity overall. This strong multivalent binding enables effective agglutination, complement activation, and pathogen neutralization.
234
How do B cells and T cells differ in the way they recognize antigens?
B cells recognize native antigens in their three-dimensional form via the B cell receptor (BCR), which binds conformational epitopes. In contrast, T cells recognize processed peptide fragments presented on major histocompatibility complex (MHC) molecules via the T cell receptor (TCR); thus, T cell epitopes are typically linear and require antigen processing.
235
Describe the general structure of the T cell receptor (TCR).
The TCR is structurally similar to the Fab fragment of a BCR. It is composed of two peptide chains (either α and β or γ and δ) with variable (V) regions that bind the antigen and constant (C) regions. Unlike antibodies, TCRs are always membrane-bound and contain only one antigen-binding site.
236
What role does the CD3 complex play in T cell receptor signaling?
The TCR itself cannot signal, so it is associated with the CD3 complex—a group of proteins (including ζ, γ, δ, and ε chains) containing immunoreceptor tyrosine-based activation motifs (ITAMs). CD3 transduces activation signals upon antigen recognition by the TCR.
237
How do CD4 and CD8 co-receptors contribute to T cell activation?
CD4 and CD8 co-receptors bind to non-polymorphic regions of MHC class II and class I molecules, respectively. Their binding stabilizes the interaction between the TCR and the peptide–MHC complex, enhancing T cell activation and ensuring proper antigen recognition.
238
What are superantigens, and how do they differ from conventional antigens in T cell activation?
Superantigens are microbial proteins that bypass the normal antigen-processing pathway. They bind directly to non-variable regions of TCRs and non-polymorphic regions of MHC class II molecules, resulting in the non-specific activation of a large percentage (5–20%) of T-helper cells. This leads to massive cytokine release and potentially harmful systemic effects.
239
Explain the concept of a polyclonal response in the context of an infection.
A polyclonal response occurs when multiple B and T cell clones are activated in response to a pathogen. Since pathogens typically display multiple antigens (and epitopes), various clones that recognize different antigenic determinants expand simultaneously, providing a broad and effective immune response.
240
What structural feature of the TCR ensures that it can only recognize antigen when it is presented by MHC molecules?
The TCR’s structure is designed to interact not only with the peptide but also with parts of the MHC molecule. This dual recognition ensures that T cells are activated only when the antigen is properly processed and presented by antigen-presenting cells (APCs) via MHC molecules.
241
How do the variable regions of antibodies (and BCRs) contribute to their specificity?
The variable regions (VH and VL) of antibodies contain hypervariable loops known as complementarity-determining regions (CDRs). These CDRs create the antigen-binding site (paratope) with unique shapes and amino acid sequences, allowing each antibody to bind specifically to its corresponding epitope.
242
What is the significance of immunoglobulin folds in antigen receptor structure?
Immunoglobulin folds are structural domains that form the basis of the variable and constant regions in both antibodies and TCRs. Their modular nature allows for the enormous diversity of antigen-binding sites required to recognize a wide array of antigens while maintaining a stable protein structure.
243
What does 'goodness of fit' mean in the context of antibody–antigen interactions?
'Goodness of fit' refers to the complementarity between the three-dimensional structure of an antibody’s antigen-binding site (paratope) and the epitope on the antigen. A better fit results in stronger binding (higher affinity), leading to a more effective immune response.
244
How do the antigen-binding properties of the B cell receptor (BCR) relate to the production of antibodies?
The BCR is essentially a membrane-bound antibody that confers antigen specificity to a B cell. When a B cell is activated by antigen binding, it can differentiate into plasma cells that secrete soluble antibodies with the same specificity. Thus, the BCR and secreted antibody share identical antigen-binding regions and immunoglobulin class (after class-switching).
245
What role does class-switching play in shaping the antibody response?
Class-switching allows a B cell to change the constant region of its antibody while retaining the antigen-binding specificity. This process enables the immune system to produce different classes of antibodies (IgM, IgG, IgA, IgE, IgD) that are tailored for various effector functions and tissue distributions, improving the overall effectiveness of the immune response.
246
Summarize how T cell receptors (TCRs) and B cell receptors (BCRs) are similar and different.
Both TCRs and BCRs share structural features such as variable and constant regions and immunoglobulin folds, and both rely on hypervariable regions (CDRs) for antigen binding. However, BCRs bind native antigens directly and can be secreted as antibodies, whereas TCRs require processed peptides presented on MHC molecules and are always cell-associated, relying on the CD3 complex for signaling.
247
What is the role of superantigens in immune responses, and why are they potentially dangerous?
Superantigens bypass the normal antigen-processing pathway by binding directly to conserved regions of the TCR and MHC class II molecules. This results in the non-specific activation of a large fraction of T-helper cells, leading to excessive cytokine release (a cytokine storm) and potentially severe systemic inflammation.
248
How does the concept of 'polyclonal response' influence vaccine design?
A polyclonal response, which involves the activation of multiple B and T cell clones recognizing various epitopes, ensures broad immunity against pathogens. Vaccines are designed to include multiple antigenic determinants to elicit this diverse immune response, enhancing protective efficacy and memory.
249
What factors determine the overall strength and effectiveness of the antigen–antibody interaction?
The overall interaction strength is determined by the affinity (strength of one binding interaction) and the avidity (combined binding strength of multiple sites). Structural complementarity, the number of binding sites, and the stability of the antibody–antigen complex all play crucial roles in the effectiveness of the immune response.
250
What is antigen processing and presentation, and why is it important for T cell activation?
Antigen processing and presentation is the process by which protein antigens are broken down into peptide fragments and loaded onto major histocompatibility complex (MHC) molecules. These peptide–MHC complexes are then expressed on the cell surface, where they are recognized by T cell receptors (TCRs). This process is essential for activating T cells and initiating an adaptive immune response.
251
What are the main differences between the endogenous and exogenous antigen processing pathways?
In the endogenous pathway (MHC class I), antigens originate from proteins synthesized within the cell, are degraded by the proteasome, and peptides are transported into the ER via TAP for loading onto MHC class I molecules. In contrast, the exogenous pathway (MHC class II) processes antigens taken up from outside the cell via endocytosis or phagocytosis, with peptides loaded onto MHC class II molecules in specialized endosomal compartments (MIIC).
252
Describe the structure of MHC class I molecules.
MHC class I molecules are found on all nucleated cells and consist of a single polymorphic α chain (with α1, α2, and α3 domains) that forms a peptide-binding groove together with β2-microglobulin (β2m). The groove, formed by the α1 and α2 domains, binds peptides that are typically 8–10 amino acids in length.
253
How are peptides generated and loaded onto MHC class I molecules?
Endogenous proteins are ubiquitinated and degraded by the proteasome into small peptides. These peptides are then transported into the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP). Within the ER, peptides are loaded onto MHC class I molecules with the help of chaperone proteins (such as calnexin, calreticulin, tapasin, and ERp57), stabilizing the complex for transport to the cell surface.
254
What distinguishes MHC class II molecules structurally from MHC class I molecules?
MHC class II molecules are composed of two polymorphic chains—an α chain and a β chain—which together form the peptide-binding groove. Unlike MHC class I, MHC class II molecules do not associate with β2-microglobulin and bind longer peptides (typically 13–18 amino acids).
255
Explain the process of peptide loading onto MHC class II molecules.
MHC class II molecules are synthesized in the ER and bound to an invariant chain (Ii) that blocks the peptide-binding groove. The MHC II–Ii complex is transported through the Golgi into endocytic compartments, where the invariant chain is degraded, leaving a CLIP fragment in the groove. The CLIP is then replaced by peptides derived from exogenous antigens with the help of HLA-DM, allowing the stable MHC class II–peptide complex to be transported to the cell surface.
256
How do the peptides presented by MHC class I and II differ in length and source?
Peptides bound by MHC class I molecules are typically 8–10 amino acids long and derived from intracellular (endogenous) proteins, while MHC class II molecules present peptides that are usually 13–18 amino acids in length and are generated from extracellular (exogenous) proteins.
257
What role do dendritic cells play in antigen presentation?
Dendritic cells are professional antigen-presenting cells (APCs) that capture antigens in peripheral tissues (such as the skin and mucosa), process these antigens, and then migrate to lymph nodes. In lymph nodes, they present processed peptides via MHC molecules to naïve T cells, thereby initiating the adaptive immune response.
258
Which T cell subtypes are activated by MHC class I and MHC class II molecules, respectively?
MHC class I molecules present antigenic peptides to CD8+ cytotoxic T cells, which then target and kill infected or abnormal cells. MHC class II molecules present peptides to CD4+ helper T cells, which help orchestrate the immune response by producing cytokines and assisting B cells and other immune cells.
259
What are the key features of the Human Leukocyte Antigen (HLA) complex?
The HLA complex is located on chromosome 6 and encodes the MHC molecules. It is highly polymorphic, polygenic, and co-dominantly expressed, resulting in extensive diversity of MHC molecules in the population. This diversity allows for a broad range of antigen presentation but complicates organ transplantation due to tissue typing challenges.
260
What is meant by co-dominant expression in the context of MHC genes?
Co-dominant expression means that both maternal and paternal alleles of MHC genes are expressed simultaneously in an individual. This increases the repertoire of MHC molecules available for antigen presentation, enhancing the immune response.
261
How does MHC polymorphism benefit a population?
MHC polymorphism ensures that a diverse range of peptides can be presented to T cells, providing resilience against a wide variety of pathogens. This genetic diversity helps protect the population from epidemics, though it complicates tissue matching in transplants.
262
Briefly describe the process of immunoglobulin gene rearrangement in B cells.
Immunoglobulin gene rearrangement is a process that occurs during B cell development in the bone marrow. It involves the random recombination of variable (V), diversity (D), and joining (J) gene segments (for heavy chains) and V and J segments (for light chains) to create a unique B cell receptor (BCR) for each B cell, generating a vast repertoire of antigen specificities.
263
How do T cell receptors (TCRs) achieve diversity during T cell development?
T cell receptors achieve diversity through a similar gene rearrangement process that involves the random recombination of V, D (in TCRβ), and J gene segments, generating a vast array of TCR specificities that allow T cells to recognize many different peptide antigens presented by MHC molecules.
264
What is the significance of somatic hypermutation in B cells?
Somatic hypermutation occurs in activated B cells within germinal centers, introducing point mutations into the variable regions of immunoglobulin genes. This process, coupled with affinity maturation, improves the binding affinity of antibodies for their antigen, enhancing the effectiveness of the immune response.
265
How do antigen processing and presentation pathways contribute to the specificity of the adaptive immune response?
The distinct pathways for processing endogenous (MHC class I) and exogenous (MHC class II) antigens ensure that T cells are activated by the appropriate type of antigen. This specificity allows CD8+ T cells to target infected or malignant cells, while CD4+ T cells help coordinate responses against extracellular pathogens, leading to a well-tailored immune response.
266
Why is the peptide binding groove of MHC molecules critical for antigen presentation?
The peptide binding groove of MHC molecules determines which peptide fragments can be bound and presented to T cells. Its structure, shaped by polymorphic residues, dictates the repertoire of peptides that can be displayed, thereby influencing the range and specificity of the immune response.
267
List some key antigen-presenting cells (APCs) involved in MHC-mediated antigen presentation.
Key antigen-presenting cells include dendritic cells, macrophages, and B cells. Dendritic cells are particularly effective at capturing antigens in peripheral tissues, migrating to lymph nodes, and activating naïve T cells.
268
How does the invariant chain (Ii) function in MHC class II antigen presentation?
The invariant chain (Ii) binds to MHC class II molecules in the ER, blocking the peptide-binding groove to prevent premature peptide loading. Ii directs the MHC II complex to the endocytic pathway, where it is degraded, allowing CLIP to be replaced by antigenic peptides with the help of HLA-DM.
269
Compare the lengths of peptides typically presented by MHC class I and class II molecules and explain why they differ.
MHC class I molecules generally present peptides that are 8–10 amino acids long, while MHC class II molecules present longer peptides, typically 13–18 amino acids. This difference is due to variations in the structure of their peptide-binding grooves, which accommodate different peptide lengths corresponding to their distinct processing pathways.
270
What role does the proteasome play in antigen processing for MHC class I presentation?
The proteasome degrades intracellular proteins (including misfolded or ubiquitinated proteins) into small peptide fragments. These peptides are then transported into the ER by TAP, where they can be loaded onto MHC class I molecules for presentation to CD8+ T cells.
271
How do the genetic features of the HLA complex contribute to the diversity of antigen presentation in the human population?
The HLA complex, which encodes MHC molecules, is highly polymorphic, polygenic, and co-dominantly expressed. This genetic diversity ensures that individuals can present a wide array of antigenic peptides, providing broad protection against pathogens. However, it also complicates tissue matching in organ transplantation.
