Download Cell-mediated immunity

Exam Format
• 100 points - 60 pts mandatory; 40 points
where 4, 10 point questions will be
chosen
• Some open-ended questions, some
short answer.
• Kuby question
Cytokines
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Terminology
How do cytokines achieve their effect?
Radius of action
Specific cytokines - also Th1 vs Th2
cytokines
 Receptor families
 Regulation of cytokine action
granuloma formation
Mucosal Immune System
 Components of the intestinal immune
system
 Barrier system
 Innate immune system
 Adaptive immune system
 Antigen transport in the intestine
 IgA
 Commensal bacteria
Primary Immunodeficiency
Diseases
Matching
lymphocytes
monocytes
DCs
microglia
CCR5, CXCR4
Activated
CD4+ T cells
Study Points for Ponzio Lectures
Cell-mediated immunity
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Interactions between Antigen Presenting Cells
(APC) and T cells, and the sites where these interactions
occur
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Compare and contrast TH subsets and the types of
immune responses in which they are involved, and the
mechanisms by which they mediate these immune
responses
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Interactions between TH1 cells and effector
Cytotoxic T Lymphocytes (CTL)
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Interactions between TH1 cells and effector
macrophages
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Mechanisms by which CTL and other cytotoxic
effector cells kill target cells
Ponzio, cont.
• Cancer immunology
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Various types of tumor-associated antigens, and
different ways they can be detected to identify malignant
cells in the body
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How T cells recognize tumor-associated antigens
and are stimulated to become activated, clonally expand,
and differentiate into effector cells
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Ways in which tumor cells avoid detection and/or
rejection by the immune system
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Strategies for cancer immunotherapy that are
based on our knowledge of how APC process and
present antigens, and how T cells recognize and respond
to antigens
Transplantation
•Transplantation is the process of transferring cells, tissues or organs, called a graft from one site to another or
from one individual to a different individual.
•Graft rejection is an immunological response displaying specificity, memory and self-nonself recognition.
•Three major types of rejection:
Hyperacute rejection, mediated by preexisting recipient (host) antibodies to graft antigens.
Acute graft rejection, in which TH cells and/or cytotoxic T cells mediate tissue damage.
Chronic rejection, which involves both cellular and humoral immune components.
•The immune response to antigens encoded within the major histocompatibility complex is the major factor in
rejection.
•Matching between a recipient and potential graft donors is determined by typing blood-group antigens and MHC
class I and class II tissue antigens (tissue typing).
•Host T cells recognize allogeneic MHC molecules in two different ways termed direct and indirect presentation.
•Direct presentation occurs when host T cells bind directly to intact allogeneic MHC molecules on graft antigen
presenting cells.
•Indirect presentation occurs when allogeneic MHC molecules from the graft cells are taken up, processed by host
antigen presenting cells and presented as peptide fragments by self-MHC.
•Graft rejection is suppressed by nonspecific immunosuppressive agents such as cyclosporin A, FK506 and
rapamycin.
•Specific immunosuppression using monoclonal antibodies are experimental approaches which act by deleting
populations of reactive cells or by inhibiting costimulatory signals leading to anergy.
•A major complication in bone marrow transplantation is graft-versus-host disease, mediated by the
immunocompetent lymphocytes within the donor bone marrow.
•The shortage of organs available for transplantation has focused attention on xenotransplantation.
Neuroimmunology
•Neuroimmunology is the biomedical discipline that centers on the bidirectional communication between the
central nervous system (CNS) and the immune system.
•CNS can affect the immune system via the autonomic outflow or the neuroendocrine outflow.
•Autonomic nervous system controls independent activities such as blood circulation, eyelid blinking and one
component is the sympathetic (noradrenergic) system.
•Sympathetic nerve fibers innervate primary (thymus & bone marrow) and secondary (lymph node & spleen)
lymphoid organs.
•Norepinephrine is the neurotransmitter released by the sympathetic nerve fibers and receptors for
norephinephrine are found on various cells of the immune system.
•Norepinephrine has numerous effects on the immune system.
•Hypothalamic-pituitary-adrenal (HPA) axis- brain stimulation results in increased IL-1 that triigers releae of
corticotrophin releasing hormone that acts on the anterior lobe of the pituitary gland. Adrenocorticotropin (ACTH)
is released by the pituitary and induces the release from the adrenal gland of corticosteroids which suppress the
immune system.
•Cytokines such as IL-1, IL-2, TGF-β and IFNs exert various affects on the central nervous system such as induce
fever, stimulate proliferation of astrocytes, and foster neural differentiation.
•Brain is an immunologically privileged site. Immune privilege is an active process associated with antigenspecific suppression of cell-mediated and humoral immunity.
•An important aspect of the neuroimmune axis is its relationship to diseases.
•Immune system is involved in the pathogenesis of numerous diseases of the central and peripheral nervous
system, such as multiple sclerosis, Guilllain-Barre syndrome, myasthenia gravis.
•Multiple sclerosis (MS) is an inflammatory, demyelinating disease affecting the myelin sheaths surrounding nerve
fibers and nerve axons. Genetic, environmental and autoimmune factors play a role in the pathogenesis of this
disease. Studies from the animal model experimental autoimmune encephalomyelitis (EAE) suggest that Th1 and
Th17 cytokines are critical mediators of the inflammation and that antibodies also play a role. The class II HLA
alleles, DR15, DQ1 are the most consistently identified genes. Interferon-β is one FDA approved therapy for MS.
•Myastenia gravis is a disease that affects the neuromuscular junction causing weakness of voluntary muscles –
eye closure, face, chewing, swallowing. The target autoantigen is the nicotinic acetylcholine receptor (AChR) and
antibodies to this receptor are found in about 90% of patients.
•Guillian-Barre syndrome is an acute demyelinating disease of the peripheral nervous system. Numerous viruses
and bacteria are implicated with the onset of disease. This disease is believed to be primarily antibody mediated.
Fitzgerald-Bocarsly - Immunity to Infectious
Diseases
• Mechanisms of host defense to different pathogens
– Bacteria, viruses, parasites: be fluent with the mechanisms if I
stressed them
– Pathways to get CD4 activation vs. CD8
• Cytosolic vs. endosome-expressed antigens
• The presence of an immune response does not always = protection
• Th1 vs. Th2 responses:
– What are Th1 vs. Th2 cells? What do they do and what do they
make? In what systems is one more important than the others?
• Host evasion strategies:
– Infectious organisms put a lot of their “energy” into evading the
immune response
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Antigenic variation - examples
Immunosuppressive cytokines
Inhibition of antigen presentation to CD8s (many viruses)
Decoy receptors
• Immunopathology: what is it and when does it occur?
Vaccines and Immunotherapy
• Distinguish passive and active therapy
– Passive immunotherapy (mostly Ab, but could be
cells) is given for immediate protection
• Quick acting
• Short-lived
• May be used acutely for known exposure or a
prophylaxis (e.g. to patients with a known Ig
immunodeficiency)
– Active immunization
• Immunize to get to a primary, then secondary response
and memory
• Type of vaccine can determine type of immune response
• Immunotherapy
– Cytokines
– Antibodies to block function of cytokines,
receptors
Types of Vaccines
• Do we want CTL?
– Then we have to get the antigen into the endogenous
processing pathway (cytoplasm to proteasome to TAP to ER
to MHC I to surface)
• Live vaccine that can infect cells - attentuation
• Viral vectors
• DNA vaccine that gets genes products expressed in the
cytoplasm
• Other strategies such as liposomes, ISCOMs
• Do we want CD4 help and antibody?
– Then we need to get antigen into the endosomal pathway
and processed and presented with MHC Class II
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Subunit vaccines
Recombinant protein vaccines
Killed vaccines
Toxoids
Conjugate vaccines
Other vaccine issues
• What diseases is it reasonable to hope to
eradicate?
– Role of non-human hosts, whether the virus
integrates,relative infectivity (higher infectivity
means more of the herd needs to be immunized)
• Adjuvants
• Compliance
• Can we make therapeutic vaccines?
• KUBY QUESTION from chapters assigned to
my lectures (Chapters 18,19)
Mechanisms Leading to Autoimmunity
No Central Tolerance
Self-reactive TH
Infectious
Agent
Decreased Tregs