Chronic Inflammation/Adaptive Immunity

CHRONIC INFLAMMATION
Characterize
d by:

1. Lymphocytes (become plasma cells pushes nucleus off to side)

2. Plasma cells
(in tissue)

Managed by:

Macrophages
1. Call more neutrophils to the area
1. Persistent infection (most common)
2. Infection with viruses, mycobacteria, parasites, fungi
3. Autoimmune disease
4. Foreign material
5. Some cancers (chronic inflammation attacks cancers)

Arises in
response to:
Immune
system
response:

ADAPTIVE IMMUNITY

T
Lymphocytes

T Lymphocytes
1. Produced in bone marrow as progenitor T cellsmature in thymus
2. TCR rearrangement in thymus to turn T-cells into:
1. CD4+ helper T Cells
2. CD8+ cytotoxic T cells
Activation Requires:
1. Binding of antigen/MHC complex
2. Additional 2nd signal

Type of TCell:
Activation of
T cells:

CD4+ Helper T Cells (help CD8 and

B-Cells)

CD8+ Cytotoxic Cells (Killers)

CD4+ Helper T Cells (bacterial infection!

Pathogen is extracellular and must be
phagocytosed)
Primary signal: Extracellular Antigen processed
and presented by:

CD8+ Cytotoxic T Cells (virus infection!

Pathogen is intracellular)
Primary Signal: Intracellular Antigen processed
and presented by:
1. Non-Professional APCs (every other cell

1. Present

Specific, longer response

Lymphocytes (produce Ab against antigens); no multinucleated cells (no neutrophils!)
ALSO use TLRs (present on lymphocytes)mediate chronic inflammation

antigen

Result of Tcell
activation:
Secrete
cytokines

B
Lymphocytes

1. Professional APCs (macrophage,

with a nucleus)
2.
MHC class I (8x1 = 8) molecules
dendritic cells, B-cells)
2. MHC class II (4x2 = 8) molecules
Secondary signal:
Secondary signal: requires a co-stimulatory
1. IL-2 from CD4+ TH1 cell
molecule
1. B7 on APC binds CD28 on CD4+ T cells
(28 7 = 4)
Result of Activation: Helps out the other guys
Result of Activation: Cytotoxic Killing by 2 ways:
1. Secrete cytokines that help
1. Secrete perforins and
inflammation = chronic inflammation
granzymeactivates caspaseinduces
2. Helps
apoptosis of target cells
a. B-cells
2. Express FasLbinds Fas on target
b. CD8+ T-cells
cellactivates apoptosis
2 subsets of Helper T-cells:
TH1 subset: helps
TH2 subset: helps BCD8+ T-cell
cell
Cytokines:
Cytokines:
1. IL-2 (T-cell growth
1. IL-4 (class switching
factor and CD8+ Tto IgG and IgE)
2. IL-5 (eosinophil
cell activator)
2. IFN- (macrophage
chemotaxis and
activator)
activation,
maturation of B
cells to plasma
cells, class
switching to IgA)
3. IL-10 (inhibits TH1
phenotype; also
secreted by
macrophages to
resolve
inflammatory
response)
B Lymphocytes
Immature B cells are produced in bone marrow
Undergo Ig rearrangement to become nave B cells that express surface IgM and IgD
2

Activation of
BLymphocytes
:
Turn B-cells into
plasma cells that
secrete Ig
antibodies

**NOTE** The original mature B Lymphocytes will express surface IgM and IgDif we want them to
express anything else, we must activate them to express a different Ig! This is what the Helper T-cells
do!
Activation of B-lymphocytes by 2 ways:
1. Goal: Do we want our plasma cells to secrete IgM or IgD? Then we can use direct activation
via antigen binding of surface IgM B-cell becomes a plasma cell that now secretes IgM
2. Goal: Do we want our plasma cells to secrete IgE, IgG or IgA? Then we need to activate TCells that will induce Ig isotype switching:
a. Primary activation signal: B-cell can present antigen to CD4+ Helper T cells via
MHC-II (REMEMBER! B-Cells are Professional APCs!)
b. Secondary activation signal: CD40 receptor on the B-cell binds CD40L on Helper TCellin turn, activates the B-cell!
c. Helper T-cell then secretes: IL-4 and IL-5 (mediates B-cell isotypes switching,
hypermutation, maturation to plasma cells)these B-cells can now secrete IgD/A/E

Result of
Activation of
B-cells:
Subtypes of
chronic
inflammation
:

GRANULOMATOUS INFLAMMATION

NON-GRANULOMATOUS INFLAMMATION

Characterized by:
1. Key cell: Epitheloid histiocytes
(macrophages with abundant pink
cytoplasm)
2. Surrounded by giant cells and rim of
lymphocytes
3. Dividing into noncaseating and caseating
subtypes

Chronic Inflammation/Adaptive Immunity Q&A

Q: How do you activate nave CD8 T cells specific for viral antigens if the virus doesnt infect the professional APC? Ex.
A:
Q: What is the defining characteristic of a granuloma?
A: Epitheliod histiocytes
Q: How do you distinguish acute from chronic inflammation in the clinical setting?
A: Acute inflammation is indicated by rebound tenderness (inflamed peritoneum), fever, non-specific pain, age (young is less
likely to have chronic inflammation), increased neutrophil count (almost never seen in chronic inflammation)

Q and A
Q: What are the two things that mediate pain?
A: PGE2, bradykinin
Q: What process is occurring in a patient that is coughing up pus eight weeks after illness?
A: Continued acute inflammation, managed by the macrophages secreting IL-8 to bring more neutrophils

(I3_034) Regulation of T Effector Cell Development and T Cell Mediated Immunity

Learning Objectives:
1. Describe how differences in initial T cell activation and the microenvironment can lead to the development of distinct effector
function.
2. Describe the specific factors which regulate different CD4 T effector cells subset development and how different effector
functions are associated with different immune responses.
3. Describe the mechanisms involved in developing and mediating cytotoxic T cell effector function.
4. Describe the differences between primary and secondary immune responses and the concept of immunological memory.

Pre-session video question: What factors regulated the development of a Th17 effector response (and not other T
effector responses) in the video?
Pathogenesis of psoriasis:
1. Injuryformation of acute lesion
2. Hypothesis: keratonocytes release self-DNA along with the antimicrobial peptides and IL-1activates dendritic cells to
secrete high amounts of the antiviral mediator interferon IFN
3. Combination of IFN and IL-1activate dendritic cells to promote T-cell differentiation (EARLY CLINICAL FINDING:
accumulation of T-cells and DC around the blood vessels
4. Overt lesion occurs when CD8 Tcells, DC, and neutrophils infiltrate the epidermis
5. Specialized subset of T cells (TH17) secrete IFN and IL-17stimulate proliferation of keratinocytesthickening of
epidermis
a. Keratinocytes release signals that act as chemoattractants for infiltrating neutrophils
6. Cross-talk between immune cells, keratinocytes, and dermal cells contribute to tissue remodeling and amplification of this
dysregulated immune response
7. Without tx, acute lesions become chronic lesions
Why does this all happen?
Studies have identified psoriasis susceptibility geneslink TH17 cells to psoriasis pathogenesis
Activation of self-antigen can cause autoimmune dysfunction!
Th17 cells make IL-17
Induced by IL-6 and TGF
6

Development depends on transcription factor RORt

Th17 cells are responsible for promoting immunity to extracellular bacteria and fungi in the skin and mucosal sites (as well
as in the gut to provide protection against GI pathogens)
Autoimmune diseases occur with these cells (i.e. IBD, MS, RA, psoriasis)

Pre-session notes:
Innate immunity: Dermis
Langerhans Cells (specialized dendritic cells)sample bacterial antigens from the environmentinflammatory or antiinflammatory, depending on need
Dendritic Cells: capture and present antigens to T cells; arms stretch out through epidermis
o Recognize PAMPS exposed by cell death
o Migrate to lymph nodes to present antigen to nave T cells, priming them to activate and differentiate into effector T
cells
o Activate T cells return to the skin and kill infected keratinocytes, control viral infection, or recruit additional immune
effector cells
o After viral infection cleared, memory T CD8+ cells persist in the epidermis to provide future protection against the
same antigen
T cells in the dermis are CD4+ cells; modulatory role
Also eosinophils, mast cells and NK cells present for allergic rxns

Epidermis
Memory T cells (the effector cells) = (more than twice the number of T cells in the skin as there are in the blood); can be
rapidly activated when encountering antigens; most are CD8+ cellscytotoxic
Keratinocytes and dendritic cells recognize pathogens
Keratinocytes release:
o antimicrobial peptides (kill bacteria directly)
o IL-1 (inflammatory mediator; activates dendrites)
o Chemokines (recruit macrophage, T cells, and?)
o T-cells return to epidermis to kill the infected keratinocytes to control infection
Disregulation of immune response in skin leads to:
1. Dermatitis & Psoriasis: lifelong inflammatory skin diseasedry scaly red patches, due to a combo of environmental and
hereditary factors
a. Autoimmune function; stressed keratinocytes released stuff that gets recognized as foreign,
2. Stressed keratinocytes

I3_035 B-Cells & Humoral Immunity

Learning Objectives:s.
1. Describe the functions and development of the 3 major subsets of B cells (conventional, marginal zone, B1 cells)
2. Descibe the regulation of affinity maturation and isotype switching during the germinal center response.
3. Describe the different effector functions of the antibody isotypes.
4. Describe how the complement system is activated by Ab and roles of complement in the immune response.