Download Immuno Review Sheet

Immuno Review Sheet
Renee Prater, 11/14/2008
Dear MSI’s,
It has been a real honor and pleasure working with such a bright and
enthusiastic class. Many of you have asked for a review sheet to try to pull
immunology together and help with studying for final exams. I have
compiled some of the information that I feel is most important (below) and
it has turned out to be LONG and still not totally complete. I am posting this
today so that you have time to review this before you leave for T-day break.
If you see parts of this that can be improved, please let me know ASAP and
I will revise and repost a new version so that the class can benefit the most
from a review document. I couldn’t possibly put everything in here, so
please go back and review all course material (and of course lecture
material from Dr. Z, A, and R) so that you are adequately prepared for the
final, and please let me know how I can modify this so that you have the
best possible material to be successful on the immuno final and beyond.
Thank you so much for your attention, enthusiasm, and patience. Happy
Thanksgiving and best wishes for your continued success! You are
amazing student doctors!
Renee P.
Lecture #1 Introduction to Immunity
Definitions:
Acute phase proteins: serum proteins produced by the liver, whose levels
increase during infection or inflammatory reactions.
Adaptive immune system: recently evolved system of immune responses
mediated by T and B lymphocytes. Immune responses by these cells are based
on specific antigen recognition by clonotypic receptors that are products of genes
that rearrange during development and throughout the life of the organism.
Additional cells of the adaptive immune system include various types of antigenpresenting cells.
Adhesion molecules: cell surface molecules involved in the binding of cells to
extracellular matrix or to neighboring cells, where the principal function is
adhesion rather than cell activation.
Allergen: an agent (pollen, dust, animal dander) that causes IgE-mediated
hypersensitivity reactions.
Antibody: B cell-produced molecules encoded by genes that rearrange during B
cell development consisting of immunoglobulin heavy and light chains that
together form the central component of the B cell receptor for antigen. Antibody
can exist as B cell surface antigen-recognition molecules or as secreted
molecules in plasma and other body fluids.
Antigens: foreign or self-molecules that are recognized by the adaptive and
innate immune systems resulting in immune cell triggering, T cell activation
and/or B cell antibody production.
Antigen receptors: the lymphocyte receptors for antigens including the T cell
receptor (TCR) and surface immunoglobulin on B cells which acts as the B cell’s
antigen receptor (BCR).
Antigen presentation: process by which certain cells in the body (antigen
presenting cells or APC, including macrophages, dendritic cells, B cells, etc)
express antigen on their cell surface (MHC class II) in a form recognizable by
lymphocytes. Lymphocyte binding to class II MHC stimulates lymphocytes to be
active, proliferate, and secrete cytokines to activate other parts of the immune
system. APCs are in skin, in lymph nodes, and in other organs. Once APCs
phagocytose pathogens, they migrate through lymph vessels to a nearby lymph
node to interact with T cells and help to activate CMI and humoral immunity.
Apoptosis: the process of programmed cell death whereby signaling through
various death receptors on the surface of cells (e.g., TNF receptors, CD95) leads
to a signaling cascade that involves activation of the caspase family of molecules
and leads to DNA cleavage and cell death. Apoptosis, which does not lead to
induction of inordinate inflammation, is to be contrasted with cell necrosis, which
does lead to induction of inflammatory responses.
B lymphocytes: bone marrow-derived or bursal-equivalent lymphocytes that
express surface immunoglobulin (the B cell receptor for antigen), and secrete
specific antibody after interaction with antigen.
B cell receptor for antigen: complex of surface molecules that rearrange
during postnatal B cell development, made up of surface immunoglobulin (g) and
associated Ig alpha-beta chain molecules that recognize nominal antigen via Ig
heavy and light chain variable regions, and signal the B cell to terminally
differentiate to make antigen-specific antibody.
Basophil: the least commonly seen polymorphonuclear leukocyte in circulation
that stains with basic dyes (dark bluish purple granules in the cytoplasm) and has
an important role in control of inflammation, such as release of histamine and
proteases such as elastase. Basophils are also an important source of IL-4,
which is an important cytokine in the TH2 pathway and humoral immunity.
Basophils are often associated with allergic reactions, and they have receptors
for IgE on their cell surface. IgE binding activates basophils.
Bradykinin: a vasoactive peptide that is the most important mediator of the kinin
system, and causes pain and leaky vessels in acute inflammation.
Cell-mediated immunity: immune reactions that are mediated by cells rather
than by antibody or other humoral factors. CMI involves T H1 activation of TC,
which are important in fighting intracellular pathogens.
Chemokines: cytokines that bind to G protein-linked receptors and are
chemotactic and have cell-activating properties.
Complement: cascading series of plasma enzymes and effector proteins whose
function is to lyse pathogens and/or target them to be phagocytosed by
neutrophils and monocyte/macrophage lineage cells of the reticuloendothelial
system. Individual complement proteins, that are produced by the liver and
normally circulate independently and in inactive form, come together in the
complement cascade to form the membrane attack complex (MAC) that lyses
infected cells or pathogens. By-products of the complement system are used as
chemokines, or as opsonins.
Co-stimulatory molecules: molecules of antigen-presenting cells that lead to T
cell activation when bound by ligands on activated T cells.
Cytokines: Soluble proteins that interact with specific cellular receptors that are
involved in the regulation of the growth and activation of immune cells and
mediate normal and pathologic inflammatory and immune responses.
Dendritic cells: myeloid and/or lymphoid lineage antigen-presenting cells of the
adaptive immune system. Immature dendritic cells, or dendritic cell precursors,
are key components of the innate immune system by responding to infections
with production of high levels of cytokines. Dendritic cells are key initiators both
of innate immune responses via cytokine production and of adaptive immune
responses via presentation of antigen to T lymphocytes.
Endothelial cells: cells that line blood vessels and lymphatic vessels. When
damaged, they release tissue factors that activate inflammation immunity.
Eosinophils: relatively uncommonly found polymorphonuclear leukocyte that
contains cytoplasmic granules that stain with acidic dyes (orange-red) and are
particularly involved in reactions against parasitic worms and in some
hypersensitivity reactions.
Flow cytometry: analysis of cell populations that are in suspension, and can be
identified and sorted (FACS) based on cell size and surface markers.
Germinal centers: an area of secondary lymphoid tissue where B cells
differentiate and undergo antibody class switching (that is, B cells first produce
IgM early in an infection, then switch to another type of immunoglobulin, usually
IgG, in a more established infection. You can tell how long a person has been
infected with an organism by looking at their ratio of IgM to IgG).
Granulocytes: neutrophils, eosinophils, basophils.
Granulomatous inflammation: macrophages, chronic inflammation. Often
areas of granulomatous inflammation are ringed by small lymphocytes.
HLA: human leukocyte antigen; human major histocompatibility complex (MHC).
Innate immune system: ancient immune recognition system of host cells
bearing germ line-encoded pattern recognition receptors (PRRs) that recognize
pathogens and trigger a variety of mechanism of pathogen elimination. Cells of
the innate immune system include natural killer (NK) cell lymphocytes,
monocytes/macrophages, dendritic cells, neutrophils, basophils, eosinophils,
tissue mast cells, and epithelial cells.
Interferons: a group of molecules involving cell signaling between cells of the
immune system, and used in protection against viral infections.
Interleukins: a group of molecules involved in signaling between cells of the
immune system.
Large granular lymphocytes: lymphocytes of the innate immune system with
azurophilic cytotoxic granules that have NK cell activity capable of killing foreign
and host cells with little or no self MHC class I molecules.
Macrophage: an important immune cell that is made in the bone marrow and
circulates as a monocyte, then becomes a macrophage in tissue. Macrophages
can act as APC, and are professional phagocytic cells that are very important in
chronic inflammation.
Natural killer cells: large granular lymphocytes that kill target cells that express
little or no HLA class I molecules such as malignantly transformed cells and
virally infected cells. NK cells express receptors that inhibit killer cell function
when self-MHC class I is present.
Neutrophils: polymorphonuclear leukocytes that are the most abundant in the
blood, and perform phagocytosis and respiratory burst (increased oxidative
metabolism) in acute inflammation.
Opsonization: a process by which phagocytosis is facilitated by the deposition
of opsonins (antibody or C3b) on the antigen.
Pathogen-associated molecular patterns (PAMPs):
invariant molecular
structures expressed by large groups of microorganisms that are recognized by
host cellular pattern recognition receptors in the mediation of innate immunity.
Some examples of pamps include LPS or endotoxin, flagellin, hemagglutinin,
teichoic acid, or unmethylated DNA (e.g., small sugars or proteins that are
present on foreign material that is not present on host cells that can be
recognized by members of innate immune system even without prior exposures)
Pattern recognition receptors (PRRs):
germ line-encoded receptors
expressed by cells o the innate immune system that recognize pathogenassociated molecular patterns.
Periarteriolar lymphoid sheath (PALS): accumulations of lymphoid tissue that
constitutes the white pulp in the spleen.
Plasma cell: a B cell that has differentiated to produce antibodies against a
specific antigen.
Primary lymphoid tissue: lymphoid organs where lymphocytes complete their
initial maturation steps: including fetal liver, adult bone marrow, and thymus.
Privileged sites: tissues that induce weak immune responses, or sites of the
body that are partly shielded from graft rejection reactions; these include the
testes, brain, fetus, and anterior chamber of the eye.
Secondary lymphoid tissue: tissues that trap antigen and provide sites for
mature lymphocytes to interact with that antigen, including lymph nodes, spleen,
mucosal-associated lymphoid tissues, gut-associated lymphoid tissues, etc.
T cells: thymus-derived lymphocytes that mediate adaptive cellular immune
responses including T helper, T regulatory, and cytotoxic T lymphocyte effector
cell functions.
T cell receptor for antigen: complex of surface molecules that rearrange during
postnatal T cell development made up of clonotypic T cell receptor (TCR) alpha
and beta chains. The clonotypic TCR alpha and beta chains recognize peptide
fragments of protein antigen physically bound in antigen-presenting cell MHC
class I or II molecules to mediate effector functions.
Tolerance: B and T cell nonresponsiveness to antigens that results from
encounter with foreign or self antigens by B and T lymphocytes in the absence of
expression of antigen-presenting cell costimulatory molecules. Tolerance to
antigens may be induced and maintained by multiple mechanisms either centrally
(in the thymus) or peripherally at sites throughout the peripheral immune system.
Be able to list the body’s natural barriers to infection (such as on the skin: sweat
glands produce sweat with high salt concentration, oil gland produce sebum with
acid pH, stratified squamous epithelium sluffs off and takes potential pathogens
with it, skin surface has commensal bacteria on it that occupies space and
discourages pathogen growth, etc; digestive system has vomiting, diarrhea,
peristalsis; urogenital system has commensal bacteria, etc).
Understand that when you are exposed to a pathogen, either the immune system
removes the pathogen and develops memory/resistance for future infection, or
you suffer from chronic illness and either die or eventually become resistant to
that organism and are able to clear the infection.
Be able to list the major organs of the immune system, relatively where they are,
what cells that normally reside there and what it looks like, whether they are a
primary or secondary lymphoid organ, and what its function is in immunity.
Know that the bone marrow has multipotential adult stem cells that may develop
into red cells (erythrocytes), white cells (= leukocytes:
neutrophils,
monocyte/macrophages, basophils, eosinophils, mast cells, dendritic cells,
lymphocytes - B and T, natural killer cells) and platelets (megakaryocytes).
Know that innate immunity is an old system, can respond to antigens that it has
never seen before because it recognizes common amino acid sequences that
are present in a large number of pathogens, that it can respond rapidly, and that
it is primarily phagocytic or killing in function. Also know that the innate immune
system has no memory and activates the adaptive immune system by antigen
presentation and production of cytokines. Know the cells of the innate immune
system: monocyte/macrophage, dendritic cell, neutrophil, eosinophil, basophil,
mast cell, NK cell (the only one that is from the lymphoid and not myeloid line).
Know that the adaptive immune system is a newer system that is antigen
specific, responds more slowly, and has memory. B cells and T cells are in
adaptive immune system.
Know the definition of the different chemicals the immune system uses to
communicate between cells (cytokine is a general term of a chemical produced
by a cell that influences the activity of another cell; a lymphokine is a cytokine
that is produced by a lymphocyte; a monocyte is a cytokine that is produced by a
monocyte/macrophage; a chemokine is a chemical produced, usually by innate
immune system, to call other immune cells to the site of infection/inflammation by
way of a chemical gradient – the chemokine concentration becomes greater in
the tissue that is closest to the site of inflammation; interleukins are another
chemical that leukocytes or white blood cells produce to talk to/activate/regulate
each other; and finally interferons are chemicals that are produced that typically
work to interfere with viral replication and also function in activation of CMI).
Dendritic cells are innate immunity – sample environment to look for foreign
antigens; if it finds a foreign antigen it phagocytoses, processes the antigen and
puts the antigenic epitope on a class II MHC molecule to present to helper T cells
(CD4 cells), to initate the adaptive immunity. If it is an intracellular pathogen it is
presented to helper 1 T cells, and through release of interferon-gamma, the
helper 1 T cell upregulates cell-mediated (or cytotoxic) immunity (via the work of
cytotoxic T cells, or CD8 cells). If the pathogen is extracellular, then the helper 2
cells are upregulated via interleukin 4, which primarily upregulates humoral
immunity (production of immunoglobulins by B cells that are transformed into
plasma cells).
Remember that macrophages and dendritic cells are not the only antigen
presenting cells: B cells can also be antigen presenting cells.
Remember that antibodies are specific to one particular antigen or epitope – this
is usually a protein, usually is about 10 amino acids long, and the antigen and
antibody fit together very specifically like a lock and key. Remember that
antibodies have a constant region and a variable region that is antigen-specific.
When B lymphocytes are mature and just being activated, they first produce IgM,
and then they undergo isotype or class switching and become full-fledged
plasma cells, which then produce IgG.
Remember that IgA is the doublet that is found primarily at the mucosal surfaces,
and guards against pathogens gaining entry into the body.
Remember that IgE is usually associated with allergy.
Cytotoxic T cells kill infected or cancerous cells with the use of their cytoplasmic
granules – perforin pokes holes in the infected/cancer cell membrane; granzyme
forces that infected or tumor cell to undergo apoptosis.
Remember that APC are the few cells in the body that can make class II MHC
molecules. They use this receptor to present antigen to the helper T cells. In
contrast, nearly all cells (except red blood cells) have MHC class I antigens. If
that cell is infected, it can put the antigenic part of the pathogen that is infecting it
onto a class I MHC molecule, and target it for destruction by a cytotoxic T cell
before it infects another neighboring cell. However, remember that healthy cells
that have degraded part of itself or another “self” cell can also present self
proteins on class I MHC. The cytotoxic (CD8) T cell has been trained in the
thymus (positive and negative selection) to only become activated and start
killing if that protein on the MHC class I receptor is foreign. If it is a self protein
the Tc cell shouldn’t do anything. IF it DOES start killing cells, then that Tc cell is
considered “autoreactive”, and suggests that there is autoimmunity.
Recognize that the immune system is a very intricate system – has a lot of
checks and balances that need to keep it in check so that there is not excessive
immune stimulation (autoimmunity), or insufficient immune stimulation (cancer
and infectious disease).
Know that the complement system consists of a series of soluble proteins in the
blood that come together in acute inflammation to do the following: chemotaxis,
opsonization, and membrane attack complex. Make sure you know the factors
that act as opsonins, as chemotactic agents, and that are encompassed in the
MAC (Dr. Zed lecture).
Be familiar with a few of the more common diseases associated with primary
immune deficiency (born with it – genetic deficiency like SCID, etc), and
secondary immune deficiency (drug or chemical or malnutrition or chronic
disease caused) such as AIDS; also be familiar with the concept of autoimmunity
and a few of the more common autoimmune diseases (lupus, rheumatoid
arthritis, diabetes). Also know that immune cells can become cancerous and
cause either solid or circulating neoplasms.
Lecture #2 Inflammation, Wound Healing, Cytokines
Inflammation is the response of vascularized tissue to injury.
The purposes of inflammation are:
1. Clean up dead cells, bacteria and other pathogens.
2.
Deliver inflammatory cells and fluids that contain clotting proteins,
chemokines, complement proteins, etc. to the area of injury.
3. Deliver growth factors that help to heal the injured tissue.
Know that acute inflammation occurs when vascular tissues are injured. There is
a release of phospholipids from the injured cell membranes, which causes the
arachidonic acid cascade (inflammation, pain); also there is a release of
histamine from mast cells and basophils that cause increased vascular
permeability, leakage of plasma and inflammatory cells to the area of injury.
Know that in acute inflammation the first step is cleaning up the debris, and the
second step is wound healing.
In acute inflammation, usually neutrophils respond first, then macrophages.
Know that mature neutrophils have segmented nuclei (like string of sausages)
and the less mature form that comes out of the bone marrow in acute
inflammation, to keep up with the demand when the mature neutrophils are
running low is called a band because the diameter of its nucleus is roughly equal
all the way around. You should see the most segmented neutrophils, then fewer
bands, then even fewer less mature neutrophils, and this is called an orderly left
shift in acute inflammation.
If an avascular tissue is injured, it is slower to heal because it depends on the
nearby vascularized tissue to help with the inflammatory process.
Five cardinal signs of inflammation:
1. Heat – due to vasodilation caused by histamine and seratonin, released by
mast cells and basophils.
2. Redness – also due to vasodilation caused by histamine.
3. Swelling – caused by edema fluid from leaky vessels – increased vascular
permeability is caused by histamine and serotonin.
4. Pain – caused by kinin system which is activated by tissue injury.
5. Loss of function.
Know the 5 cardinal signs of inflammation are primarily due to the tissue damage
and the resulting vasodilation and fluid and cell exudation.
When tissues are damaged, endothelial cells, macrophages, and neutrophils
release proteins that cause mast cell degranulation and histamine release, which
causes vasodilation (actually to be more precise, dilation of venules to deliver
cells and proteins to the area of injury, and constriction of arterioles to help stop
bleeding).
Cells of the innate immune system (macrophages, natural killer cells, etc)
recognize PAMPS on bacteria (such as hemagglutinin on influenza virus, flagellin
on flagellated bacteria, teichoic acid on G+ bacteria, LPS on G- bacteria, and
unmethylated DNA, which is foreign to host cells) and bind the PAMPS with their
Toll-like receptors. This helps to upregulate both innate and adaptive immunity.
Proteins that are helpful in acute inflammation: antibodies to activate the
classical complement cascade and for opsonization; complement proteins for
MAC and for opsonization and chemotaxis, kinins for vasodilation and pain, and
the clotting or coagulation cascade to help stop the bleeding, which is usually
accompanied by the fibrinolysis cascade, which breaks down excess fibrin to
prevent thrombus formation and potential thromboembolism. TPA is example.
Cells that are helpful in acute inflammation: neutrophils (purulent or pus
inflammation), lymphocytes (more chronic inflammation along with
macrophages), and eosinophils (allergy or parasitic infection). Remember the
acute phase proteins are released by the liver in acute inflammation, and they
include C reactive protein, coagulation proteins, complement proteins, etc.
Remember the inflammatory cytokines: IL-1, 2, 6, and 8, and TNF alpha and IFN
gamma. Remember that IL-4 is related to upregulation of humoral immunity.
Chemokines are cytokines (proteins made by immune cells) that attract other
immune cells by a concentration gradient to the site of inflammation.
Antibodies can serve two functions: opsonins (attach to antigens to make them
easier to phagocytose or eliminate) and neutralizing antibodies (bind to antigens
to prevent them from entering and infecting a cell). The most important opsonins
are C3b and IgG.
Be able to describe each type of leukocyte as far as their cytoplasmic and
nuclear features, and know what each one does:
Neutrophil: pale granular cytoplasm, segmented nucleus, does phagocytosis
and respiratory burst (releases reactive oxygen and nitrogen to kill pathogens).
Eosinophil: bright red staining granular cytoplasm, segmented or bilobed
nucleus, is associated with allergic and parasitic inflammation.
Monocyte: larger, pale blue “ground glass” cytoplasm, kidney bean-shaped
nucleus, does phagocytosis and releases cytokines; tissue form is macrophage.
Lymphocyte: small round cell with scant blue cytoplasm and round nucleus.
Functions to kill infected cells (Tc) or make antibodies (B cell/plasma cell) or help
the humoral and CMI systems (Th).
Mast cells: larger cell, pinkish-purple granular cytoplasm, releases histamine in
acute inflammation.
Remember the types of inflammation and the cells/characteristics that
accompany them: granulomatous (macrophage), fibrinous (in serous cavities),
purulent/suppurative (neutrophil), serous (blisters – fluid), and ulcerative (large
defect in mucosa or epithelium).
Know the basic steps in leukocyte extravasation, or the sequence by which
neutrophils leave the vessels and enter the tissues (margination to the
endothelial surface, rolling, tight adhesion, diapedesis/extravasation, etc):
1. Margination
2. Rolling
3. Adhesion to endothelium
4. Diapedesis/extravasation/transmigration (synonyms)
5. Chemotaxis
6. Leukocyte activation
7. Phagocytosis
Leukocyte deficiencies:
1. Bone marrow is not producing enough
2. Stress/corticosteroids/absence
of
adhesion
molecules
prevents
margination and extravasation of neutrophils into tissue
3. Neutrophil can’t phagocytose foreign material
4. Neutrophil can’t digest phagocytosed material in phagolysosome
5. Phagocyte can’t release reactive oxygen species
Remember that chronic inflammation is a pathologic condition (as compared to
acute inflammation which is actually HELPFUL to the body). Know that chronic
inflammation is generally pathologic, and results when the infection/inflammation
cannot be cleared by acute inflammation.
Chronic inflammation typically has macrophages in the center, and small
lymphocytes ringing the area of inflammation. Make SURE not to confuse
granulomatous tissue, or granulomas, with GRANULATION tissue, which is a
mixture of new blood vessels and collagen-forming fibroblasts, that are important
in healing.
Examples of chronic inflammatory stimuli are things that are difficult for the body
to break down such as silica from old breast implants, asbestos, tuberculosis or
other larger organisms, suture material, etc.
Macrophages can have several appearances: foamy, epithelioid, multinucleated.
In wound healing, the major steps in healing are inflammation, proliferation, and
remodeling, and these three steps usually overlap.
Proliferative phase entails fibroplasia (fibroblasts make type III collagen, which is
a scaffold for new blood vessel formation and for cell migration into the area; this
is later replaced with type I collagen that is stronger, and is aligned along tension
lines. Fibroblasts commit apoptosis at the end of wound healing. Special
fibroblasts called myofibroblasts help with wound contraction, and then also
commit apoptosis after wound healing is complete.
Epithelialization is the process of the epithelial cells regrowing over an area of
injury. If the injury is superficial, then the basal epithelial cells that reside just
above the basement membrane, can repopulate the epithelial surface. However
if the defect went below the basement membrane and into the dermis, then the
new epithelial cells have to grow into the defect from the healthy peripheral
tissues.
First intention healing is when there was a small, usually clean defect (such as a
surgical cut), where the distance between the two healthy sides is short, and
wound healing is fast and does not leave a bad scar. First intention healing is
when the two sides of the wound are closely apposed, as with suturing or
stapling; these wounds tend to heal more quickly and leave a smaller scar. In
contrast, second intention healing is where there is a larger or irregular defect
such as an ulcer or a large abrasion, and so there is a larger distance that has to
be covered in order to heal the defect. This usually results in a longer healing
time, incomplete repair of the defect, and leaves a permanent, larger scar.
Remember the steps in wound healing: inflammation, neovascularization (new
vessels), fibrosis, remodeling.
Remember that once the inflammation is
subsiding, growth factors like transforming growth factor (TGF) further suppress
the immune system and encourage wound healing. Remember examples of
dysregulated wound healing: keloid, hypertrophic scar. In contrast, second
intention healing is when there was a large, wide defect such as an ulcer or large
abrasion.
Review factors that retard wound healing such as concurrent disease, age,
malnutrition, etc.
Be able to recognize signs of pathologic wound healing such as dehiscence,
keloid, excessive contracture, and dystrophic calcification.
Know what an abscess is (collection of neutrophils/pus that is surrounded by a
tough fibrous capsule). It is difficult for antibiotics to penetrate abscesses,
Lecture #5 Cellular Interactions in Immunity
(you may find that some of the information in the rest of the lectures has already
been covered above in the prior lectures’ reviews)
Adenoids are pharyngeal or nasopharyngeal tonsils, secondary lymphoid organs,
and if they are enlarged they can obstruct the nasal passages and disrupt
breathing. Surgery is adenoidectomy.
Tonsils are secondary immune organ in the oropharynx that sample for
pathogens coming in through the nose and mouth. Tonsils have crypts, and
contain mainly lymphocytes and macrophages. Increased macs or neutrophils is
tonsillitis, and may require antibiotic or surgical therapy. Tonsil has stratified
squamous epithelium (vs. adenoid which has ciliated respiratory epithelium)
because there is more trauma from food going past the tonsils.
Thymus is the primary lymphoid organ that “schools” immature T cells from the
bone marrow in positive (being able to bind antigens with high affinity) and
negative (won’t respond to self proteins) selection. Those that fail this schooling
are removed by apoptosis. Those that succeed can leave the thymus and go to
secondary lymphoid organs or circulate in the blood.
Remember that
autoimmunity results if those that fail negative selection are permitted to leave
the thymus.
Lymph node filters lymph, which is fluid/plasma that has escaped the vasculature
and needs to re-enter the venous system. The lymph vessels are open ended in
the tissue and have a series of lymph nodes (secondary lymphoid organs) in a
chain along the vessel that looks for pathogens in the lymph. If pathogens are
found the B and T cells in the lymph nodes are activated to fight the infection.
There are also a few macrophages in normal lymph nodes, but increased
numbers of macs or increased numbers of neutrophils means inflammation and
is called lymphadenitis. Lymph nodes can also be used to see if cancer has
spread from a primary tissue through the lymphatic system and beyond. These
nodes are called sentinal nodes (like with breast cancer). Also remember that
lymph fluid is pumped by skeletal muscle contraction, since it is not directly
connected to the heart. Lymph vessels also have one-way valves to discourage
back flow. If there is excess lymph production, or if there is a problem with
drainage, then you get edema.
Spleen is secondary lymphoid organ that has red pulp (which destroys old red
cells and is a storage for additional blood in case of acute hemorrhage), and
white pulp, which is the immune component of the organ. The white pulp tends
to concentrate around vessels as periarterial lymphoid sheaths (PALs) to look for
antigens in the blood.
Peyer’s patch is large oval lymph tissues (secondary lymphoid organ) in the
digestive system, mostly in the ileum.
Peyer’s patches contain high
concentrations of B lymphocytes that make IgA to protect the mucosal surface
from invading lumenal pathogens.
Appendix is blind ended tube near junction of small and large intestine that
contains lymphoid material (secondary lymphoid organ). Inflammation is
appendicitis, and is considered a medical emergency if it ruptures.
Bone marrow is primary lymphoid organ that makes hematopoietic cells, and
schools the B cells in positive and negative selection, as the T cells are schooled
in the thymus. In acute inflammation, the bone marrow increases production of
neutrophils, then monocytes and lymphocytes, to keep up with the demands of
the infection/inflammation.
Endocytosis can be divided into pinocytosis (engulfing fluid, drinking) and
phagocytosis (engulfing solid particles, eating).
Lecture #6 Tolerance and Programmed Cell Death
Remember that with APC/helper T cell interaction (CD4) the APC has the MHC
class II with processed antigen on it, and the T cell has T cell receptor and coreceptor (CD4) for specific binding; the purpose of this is to activate helper T cell
and initiate adaptive immunity. The infected cell presents foreign antigen on
class I MHC molecule to cytotoxic T cell receptor with co-receptor (CD8) for
specific binding. The purpose of this is for the T cell to kill the infected cell.
Regulatory T cells, or suppressor T cells, downregulate the immune system at
the end of the inflammatory process, and do so either by inducing apoptosis or
by other methods. Usually T cell suppression is encouraged by presence of
growth hormones like TGF that signal when inflammation is winding down and
healing is beginning. Another signal for immunity to quiet down is when there is
no co-stimulation of antigen presenting cells, so they stop producing
inflammatory cytokines and there is less activation of lymphocytes. When cells
are poorly activated, they become anergic and die.
Remember that a few of the T cells and B cells remain after the immune
stimulation is over; these are memory cells that are antigen specific and will
respond more quickly the next time the body encounters that pathogen.
Immune suppression can be inborn (primary) or acquired by disease, drugs, etc.
Allergy is basically an over-enthusiastic response to a pathogen.
Autoimmunity is an inappropriate response against self proteins.
Lecture #7. Defense against Microbes
Pathogen can cause disease in an otherwise healthy person; an opportunistic
infection is where a commensal (normally harmless) organism takes advantage
of someone who is immunocompromised, and causes disease, where it could not
cause disease in an immunocompetent individual.
Remember the four major plasma enzyme systems and what they do:
Complement: membrane attack complex, opsonin, chemotaxis
Coagulation: blood clots
Fibrinolysis: breaks down clots, makes FDPs
Kinin: vasodilation, blood pressure, pain – bradykinin
Know the function of these mediators in acute inflammation:
prostaglandin, complement, bradykinin.
histamine,
Gram positive bacteria have peptidoglycan which is polysaccharide capsule
which prevents complement lysis and is poorly immunogenic (need conjugate
vaccine to prevent this infection). Teichoic acid is immunogenic.
Gram negative bacteria have thin peptidoglycan layer so susceptible to
complement; have lipopolysaccharide or endotoxin to help fend off the immune
cells, but LPS is immunogenic.
Extracellular pathogens are killed by antibody neutralization, opsonization and
CMI, and complement.
Intracellular pathogens are killed primarily by cell mediated immunity.
Those intracellular pathogens like mycobacterium that have ways to evade
immune system (have a lot of lipid in the cell wall – mycolic acid - and can
prevent phagosome from binding with lysosome for bacterial destruction). But
cell wall also has proteins in it that are immunogenic so can be killed by CMI.
Spirochete bacteria are extracellular so killed by humoral immunity. No cell wall,
just few proteins on cell membrane that are immunogenic.
Viruses are all obligate intracellular pathogens, so are killed primarily by CMI.
They can escape immune system destruction by antigenic drift (changing a
single codon in their DNA over time) or antigenic shift (changing a whole
sequence of codons in their DNA over time). That way the immune has to start
over and build up new immunity against that changed virus, because the memory
cells won’t recognize after antigenic variation.
Fungal infections usually occur in immunocompromised patients. Several are
intracellular (CMI), most are extracellular (humoral).
Most parasites are big (either single celled protozoa or multicelled parasites).
Mainly humoral immunity, eosinophils, IgE.
Lecture #8. Major Histocompatibility Gene Complex
T cell receptor for antigen only interacts with antigen when the antigen is bound
on the APC cell surface and it is bound to an MHC molecule.
If APC phagocytoses a foreign pathogen, processes it, and puts the antigen up
on the cell surface on a class II MHC molecule then a helper T cell will bind and
become activated. Helper T cells responding to an intracellular antigen will
differentiate into Th1, with stimulation from interferon gamma, and will initiate
CMI. If the helper T cell is responding to an extracellular antigen, then it will
differentiate into a Th2 then it will be further activated by IL-4 and will initiate
humoral immunity.
If the APC or any other nucleated cell becomes infected with that pathogen and
needs to die before the infection spreads to other cells, it puts that antigen up on
the cell surface in association with MHC class I. A cytotoxic T cell recognizes and
kills that cell (CMI).
If the APC or other nucleated cell has degraded old worn out cellular components
and presents THAT self protein on MHC class I, the T cell should recognize that
as self and ignore it. If that T cell becomes activated, that is autoimmunity.
B cells can also be APCs. Remember that when they are mature B cells and are
activated they produce IgM. Then they undergo isotype switching and start to
make IgG when they are full fledged plasma cells.
Clonal expansion is the rapid multiplication of activated T cells to more effectively
fight the infection. Of all the cells in a particular clone, they all recognize the
same antigen. Although there may be many sets of clones against one pathogen,
as bacteria, viruses, parasites, etc have many epitopes that the immune system
can consider as immunogenic.
MHC class III is actually part of complement, not a receptor that presents
antigen.
The reason that each one of our MHCs are different (polymorphism) is an
evolutionary protection: if we all have varying susceptibilities and resistance to
different diseases by having polymorphic MHCs then at least a segment of the
population should be able to survive most of the infections that we might
encounter. But the reason transplants fail without immunosuppression is
because our MHCs are so polymorphic and we consider each other’s as foreign
and reject it.
Lecture #9: Primary Immune Deficiency
Primary immune deficiency is rare, and is usually associated with antibody (B
cell, humoral immunity) deficiency.
Primary and acquired (secondary) immune deficiency often present with similar
clinical signs: recurrent infections and infections with low-virulence organisms
(opportunistic infections).
Severe combined immunodeficiency (SCID) occurs when both cell-mediated and
humoral immunity are both impaired – either an absolute lack of B and T cells, or
B and T cells that are physically present, but are dysfunctional. For example,
SCID can occur with a MHC class II deficiency, which impairs antigen
presentation, and therefore would impair both arms of the adaptive immune
system.
You never want to give a modified live vaccine to a SCID patient.
Kids may be born with an inborn error of B cell production or function. But more
commonly, we may see a transient inability of babies to produce
immunoglobulins. Often they grow out of this and so no treatment is necessary.
If you have a deficiency of IgA, you are at greater risk of developing respiratory
or gastrointestinal infections, because IgA works at the mucosal surface to
reduce infections that cross mucosal barriers.
Problems with neutrophils may include lack of production or maturation of
neutrophils in the bone marrow, improper formation of cytoplasmic granules that
may reduce the ability of the neutrophils to perform respiratory burst, or problem
with neutrophil extravasation from the blood vessels, which may be due to
improper adhesion to the endothelium or inability to squeeze through the leaky
endothelial spaces to enter the tissue.
Lecture #10: Acquired Disorders of Immune Deficiency
Acquired immune deficiency is rarer than primary immune deficiency. Some of
the causes of acquired immunodeficiency are malnutrition, aging, chemical or
drug exposures (including alcohol), and concurrent diseases.
Malnutrition may include protein, vitamin, or other micronutrient deficiency.
Alcoholics often look like malnutrition patients as far as their immunodeficiency
diseases, and malnutrition can affect all parts of the immune system (innate,
adaptive, complement, etc).
Often we don’t see acquired immunodeficiency associated with disease because
there are so many redundancies in the immune system that if one arm is not
working properly, other parts of the immune system will make up for that deficit.
Lecture #11: Immunopathology of AIDS
HIV is retrovirus, caused predominantly by HIV-1 in developing and first world
countries (HIV-2 is endemic in Africa but is less virulent than HIV-1).
HIV is transmitted sexually in blood and semen and through breast milk.
Not thought to be spread by saliva (kissing), or by mosquitoes.
Don’t worry about learning the statistics that are in this lecture for my test –
I just gave you rough estimates of the incidence of AIDS in this country and the
world to give you an idea the severity of the problem. What I would like you take
away from this is that HIV is not under control, and the incidence is growing in
the older population, and in minorities such as African Americans and Hispanics.
Remember that HIV is preventable and is influenced by societal, cultural, and
economic factors.
HIV was thought to originate as a zoonotic disease, transferred from
chimpanzees to man in Africa in the late 1970’s, and was identified when
physicians saw an increased incidence of weird diseases (pneumocystis,
Kaposi’s sarcoma, etc).
HIV predominantly affects CD4 (helper) T lymphocytes, although it also affects
many other cells in the immune system, and throughout the body.
Know the non-specific physicochemical barriers that normally protect you from
HIV infection (skin properties, secretions, acute phase proteins, etc).
Neutrophils are typically normal in early HIV infection, and can be protective even
in late-stage disease if the body keeps producing neutrophils. But if HIV affects
neutrophil production or maturation in the bone marrow and you get neutropenia,
then the neutrophils will not be able to protect against HIV infection. (this is an
example of how if one arm of the immune system, e.g., CD4 lymphocytes, are
not working properly, the immune system has redundancies, e.g., innate immune
cells such as neutrophils, that can help to overcome problems with another arm
of the immune system. But when BOTH are non-functional, the patient suffers
overt clinical signs such as increased susceptibility to secondary disease). Over
½ of AIDS patients have neutropenia, and many more who are not neutropenic
still have dysfunctional neutrophils that further increase susceptibility to
secondary infections. AIDS patients with neutropenia tend to be more highly
susceptible to strep and aspergillus infections. HIV is also associated with
problems with macrophages (so decreased antigen presentation, and decreased
phagocytosis), problems with NK cells, and problems with complement system.
Lecture #12 Immunologic Testing
CBC – complete blood cell count. Slide must be monolayer, and count white cells
in multiples of 100, calculate % of each white cell. Increased neutrophils
(neutrophilia) means inflammation (or stress). Increased band neutrophils
means early active inflammation (left shift). Eosinophilia allergy or parasitic
infection. Monocytosis usually means established or chronic inflammation.
In biochemical blood profile, look at amount of protein. If hyperproteinemia, do
serum protein electrophoresis (separate mixture of proteins based on their
surface electrical charge). A peak is albumin, B peak is acute phase proteins
(complement, coagulation proteins, C reactive protein, etc), C peak is IgM (early
infection, D peak is IgG (more established infection - >96 hrs approximately).
Ways to detect antigen: agglutination – use monoclonal antibodies into a patient
sample that has particulate/solid antigens. Immune complexes get “glued”
together – agglutinate – into a clump you can see visually (can’t see individual
antigen-antibody immune complexes).
Precipitation uses monoclonal antibodies to find soluble antigens in solution.
Enzyme linked immunosorbant assay – ELISA – coat bottom of well with
monoclonal antibody, then add patient sample, then “sandwich” the antigen in
with another layer of antibody that is labeled with something you can see
(chromogen).
Immunochemistry – put monoclonal antibody on a fixed piece of patient tissue
that has been sliced thinly. Antigen- antibody complex lights up.
Immunoelectrophoresis – first separate antigens in patient sample using
electrical charge, then put antibody on the side and the antigen and the antibody
migrate towards each other. Where they meet there is a line of immune
complexes.
Western blotting separates antigens by molecular weight (size) then you can add
antibody and the immune complex lights up.
Affinity chromatography uses antibody-coated latex beads in a column – dump
the patient sample with suspect antigen into the column, the antigen that
matches that antibody sticks to the antibody and bead and the rest washes away.
You can also detect the RNA of a protein (antigen) by studying the RNA of a
patient sample that may contain the antigen. This is called PCR.
Epitope mapping is a way to determine which antigens on the surface of a
pathogen would be most immunogenic. Those can be put into a vaccine.
Detection of antibodies – either add the specific antigen to find that antibody, or
make a monoclonal antibody against the ANTIBODY of interest (remember
antibodies are proteins so you can make an antibody to another antibody – called
anti-IgG, for example, or secondary antibody).
Agglutination – same principle if you are looking for an antibody in a patient
sample that is attached to something solid (like an RBC), either add the antigen
or an antibody against the antibody and they all stick together and agglutinate
into a clump you can see.
You can also detect soluble antibodies in solution using precipitation.
You can also do ELISA by coating the bottom of the well either with the antigen,
or more commonly, with a secondary antibody against the antibody you are
interested in finding. Then you “sandwich” the antibody you are trying to find with
more secondary antibody that is labeled with something you can see.
Immunoelectrophoresis: put patient sample with mixture of antibodies in, apply
electric current to separate antibodies, then add either antigen or secondary
antibody on the sides. When they diffuse towards each other and meet in the
area of equal concentration, there is a line.
Western blot is where you separate a mixture of antibodies by molecular weight.
You can also detect immune complexes by ELISA or fluorescence. Immune
complexes that the macrophages can’t eat will deposit in vessels, kidney, joints.
Monoclonal antibodies are made by injecting antigen into a lab animal and letting
their immune system make the antibody to that specific antigen. Then you bleed
the animal and purify the particular antibody. Monoclonal antibodies can be used
both to diagnose antigens or antibodies, or can also be used therapeutically to
neutralize antigens or toxins (botulism, tetanus, rabies, snake venom).
You can separate white cells from blood using buoyancy or flow cytometry/cell
sorting to test the function of each group of white cells.
Remember: neutrophils phagocytose and produce reactive oxygen/nitrogen
species.
monocytes/macrophages phagocytose and produce cytokines
lymphocytes proliferate and produce cytokines.
So you can test those functions to see if the cells are working properly.
We also have animal models of many human immunologic diseases, to study
about them so that we can better understand the disease in humans.
Lecture #13: Vaccination and Immunotherapy
Know difference between passive and active immunization. Passive
immunization is directly transferring antibodies from one person to another –
natural – through placenta or breast milk (IgG) – remember neonatal gut has
specific receptors for Ig, that are lost within the first few months. Or injected to
counteract toxin or virus – ex. botulism, tetanus, rabies, snake venom.
Active vaccination means injecting small amounts of the antigen and
encouraging the body’s own immune system to make its own antibodies against
that antigen.
You give most childhood vaccines after 2 months when: baby’s immune system
can respond and when mom’s antibodies are lower so that they don’t just bind to
and neutralize the vaccine antigen.
Most vaccines are given in shots (parenterally) – to stimulate IgG. Others are
given intranasally to stimulate IgA and mucosal immunity.
Modified live vaccines – live whole virus that is less virulent but still encourages
strong and long-lasting immunity. May have contaminants and you have to be
careful of storing the vaccine properly so that it doesn’t die and become less
effective.
Killed vaccines have heat or chemical denatured whole pathogens. Less effective
vaccines so often multiple doses are needed. Also often adjuvants or immune
stimulants are needed to make the vaccine more effective. Some can be given
to pregnant women, unlike MLV vaccines.
Toxoids are inactivated toxic compounds that are immunogenic. They are not the
organism themselves.
Recombinant subunit vaccines are made from only the immunogenic parts of the
organism, not the whole organism itself. May use epitope mapping to develop.
Conjugate vaccines are made against a normally non-immunogenic part of the
organism, such as the polysaccharide capsule of the Gram positive bacterium.
The sugar is conjugated to a protein which is immunogenic. Then eventually the
immune system not only recognizes the protein but also the sugar as
immunogenic and then can respond to just the sugar if a future infection occurs.
Recombinant vector vaccine – take nonvirulent virus and add the immunogenic
DNA part of the vaccine.
DNA vaccine – inject DNA and immune system mounts an immune response
against the DNA.
There are some controversies with vaccination
Parasitic vaccines are difficult to develop, but parasites have many many
epitopes because they are big.
Immunopharmacology – use upregulation or downregulation of immune system
rather than drugs to treat disease. Used in cancer and in infectious diseases.
Immune suppression can be used, especially in transplant biology.
Lectures #18 and 19: Transplantation and Transplant Rejection
During development and early postnatal life, the body learns to recognize self
from non-self. One of the most polymorphic molecules our body makes is the
MHC molecule, and this is why transplantation biology is so difficult.
The easiest tissues to transplant are those that have the fewest antigens on
them, and ones that are relatively avascular. So… corneal transplants and red
blood cell transfusions were among the earliest successful transplants.
Have an idea which organs can be transplanted, and which ones can come from
living donors (e.g., lung, liver, skin, kidney, etc) and which ones can be
autologous transplants (e.g., skin in burn victims, bone marrow stem cells in
patients with cancer, etc.)
Know the terms autograft, syngraft or isograft, allograft, and xenograft.
Know the difference between transplant rejection (donor immune system
rejecting the transplanted tissue) and graft vs. host disease (where lymphocytes
within the transplanted tissue attack the immunosuppressed host).
Know the different types of tissue typing methods (serologic, mixed leukocyte
reactions, and genotyping), and which one is fastest and most precise, to
minimize graft rejection (that would be genotyping), and in which instances tissue
typing would be helpful or not helpful (e.g., cornea –no need to cross match
because it is an avascular tissue and is not likely to be rejected; no time to cross
match in a life-saving transplant such as heart or liver – you just have to really
immunosuppress those patients for life; but in instances when you have time, like
in a bone marrow transplant, there are good reasons to try to take the time to
match, to reduce the incidence of graft rejection or graft vs. host disease).
Be able to explain the idea of xenogeneic transplantation, and the positive and
negative aspects of this technique (e.g., positive is that we can use pig or other
animal body parts to transplant into people which will help to reduce the number
of people who die every year waiting for a transplant; but negative is that the
tissue may harbor zoonotic disease, which could be devastating when
transplanted into an immunosuppressed transplant patient).
Know the immune privileged sites of the body (anterior chamber of the eye, hair
follicles, brain, testes and fetus).
Be able to explain the significance of an Rh- mom and an Rh+ dad, and an Rh+
baby, and how that scenario might negatively impact the second child because
the mom’s body would have made antibodies against Rh and those antibodies
could attack the second baby.
Be able to define first and second set rejection, and know what hyperacute (preexisting antibodies), acute (CMI), and chronic rejection (both humoral and CMI,
happens over months to years) terms mean and their significance to the patient.
Know that once chronic rejection has occurred, immunosuppression will not help
because the damage is already done.
Know those proinflammatory cytokines that are so important: IL-1, 2, 6, 8, IFNgamma, and TNF-alpha.
Lecture #20 Transfusion Reactions
The definition of blood transfusion is transfer of blood or blood products from one
person’s circulation to another’s. Transfusion can be used to treat hemorrhage
from trauma, infection, or bleeding disorders, or to replenish red cells due to
increased red cell destruction, as with hemolytic anemia, or if there is inadequate
production of red cells in the bone marrow.
Red cells have fewer antigens on their surface than nucleated cells (remember
they DON’T have MHC class I or II on their surface, and that is the protein that is
the most polymorphic, and causes the most problems with rejection of
transplanted tissue), so therefore, it is easier to match people for blood
transfusion than it is to match someone for an organ transplant.
The major antigens on red cells are A, B, and Rh factor (there are also minor red
cell antigens that I am not going to hold you responsible for this test).
So, if you are A (e.g., AA or AO), you have A antigens on your red cells, and your
body makes anti-B antibodies, and you can receive A or O blood.
If you are B (e.g., BB or BO), you have B antigens on your red cells and your
body makes anti-A antigens, and you can receive B or O blood.
If you are AB, you have A and B antigens on your red cells and you can receive
A, B, AB, or O blood (universal recipient)
If you are O, you don’t have A or B antigens on your red cells and you can ONLY
receive O blood (universal donor).
Rhesus (Rh factor) is the second most significant blood antigen (protein) that is
on the surface of red cells of most people (more common to be Rh+ than Rh-).
Refer back to lecture 18-19 review notes for explanation about Rh factor in
pregnancy.
Know that the test we use to cross match blood for compatibility in a transfusion
is agglutination. Also remember that when we do transfusions, we usually only
transfuse red cells (or platelet-rich plasma) because these cells do not have
nuclei, and therefore do not have MHC class I or II on them, so are less likely to
cause an immune reaction. We hardly ever transfuse white cells because of the
problem with immune reaction.
Be able to recognize the signs of an acute hemolytic reaction: fever, chills,
flushing (acute phase response), cardiovascular signs such as tachycardia,
hypo- or hypertension, nausea, and burning or bleeding at the IV site). Know
that the mechanism behind this is IgM antibody against donor antigens due to
donor-recipient incompatibility. If you take a sample of that patient’s blood, you
will see red plasma (hemoglobin from lysed red cells). You may also see
hemoglobin in the urine, which is harmful to the renal tubular epithelial cells.
Know what transfusion-related acute lung injury is (immune complexes that
deposit in vascular bed of lung tissue and cause an inflammatory reaction,
plasma leakage, and pulmonary edema).
Be able to list some of the more common transfusion-related infectious diseases,
such as hepatitis, HIV, cytomegalovirus, west nile virus, and other rare ones.
Lecture #22: Systemic Sclerosis, Sjögren’s Syndrome
Scleroderma is a chronic immune disease that results in edema, endothelial
targeting, perivascular accumulation of T cells, release of proinflammatory
cytokines, and ultimately fibrosis (collagen deposition) in the skin (esp hands).
Thought to be triggered by cytomegalovirus (CMV) or exposure to organic
solvents, or microchimerism.
First you get swelling (edema), then skin becomes thick and hard (fibrosis).
Often you get flexion contractures because of tight skin. Blood vessels also look
mottled because of the perivascular lymphocytic cuffing and telangiectasis.
Remember that 90% of scleroderma patients also get Raynaud’s phenomenon
(vasospasm in fingers and toes that causes them to turn blue).
Systemic sclerosis is multisystemic scleroderma – affects musculoskeletal
system (joint pain, arthritis, myopathy), pulmonary system (dyspnea,
nonproductive cough, interstitial fibrosis in lower lung lobes, pulmonary
hypertension), GI (GERD, dysphagia, malabsorption and bacterial overgrowth,
and colitis) and renal systems (due to hypertension, microangiopathic hemolytic
anemia).
Remember CREST syndrome (calcinosis, Raynaud’s syndrome, esophageal
dysmotility, sclerodactyly, and telangiectasis).
Diagnosis of systemic sclerosis is by demonstration of antibodies.
Sjögren’s syndrome is autoimmune disorder where autoimmune CD4 T cells
attack moisture-producing glands that produce tears and saliva (affects eyes,
mouth, throat especially, but also affects kidney, GI, vessels, etc)
Tests: anti-nuclear antibody and rheumatoid factor tests.
Treatment: symptomatic and immunosuppressive.
Lecture #23 and 24: Autoimmune Disease, Lupus, Rheumatoid Arthritis
Be able to list the major factors involved in autoimmunity, such as genetic
predisposition (mostly in MHC molecules), molecular mimicry, dysregulation of
cytokines or hormones, defective T cells, and pre-existing defects in the target
organs.
Know that systemic lupus erythematosus (SLE or lupus) is called the great
imitator. It is a multsystemic autoimmune disease that is thought to be a type III
hypersensitivity reaction, and can be triggered by UV radiation, infectious agents
such as bacteria or viruses, or chemicals such as drugs (antidepressants,
antibiotics).
Symptoms of lupus include general malaise, malar skin rash, musculoskeletal
joint pain, anemia and other blood abnormalities, various cardiovascular,
nervous, and pulmonary problems, as well as renal – membranous
glomerulonephritis.
Be familiar with the 11 criteria for lupus, and know that 4 of them must be
minimally present for the diagnosis of lupus.
Know about some of the more organ specific autoimmune diseases such as
Hashimoto’s thyroiditis as a cause of hypothyroidism in women more than men.
Know that there are genetic, environmental, and immune causes for this
disorder, and know the symptoms and diagnosis as well as treatment.
Autoimmune diabetes mellitus is a reaction to self-islet cells. Often misdiagnosed
as type 2 diabetes but it is actually loss of cells that produce insulin, not insulin
resistance like with type 2 diabetes. Diagnosis is with low c-peptide levels, and
treatment is symptomatic (insulin replacement).
Myasthenia gravis is an autoimmune disorder that affects skeletal muscle cells
(actually against acetylcholine receptors at the post-synaptic junction). Diagnosis
is identification of autoantibodies at the post-synaptic junction as well as strength
tests. Treatment is immunosuppression and cholinesterase inhibitors (which
prolong the action of acetylcholine at the post-synaptic junction).
Rheumatoid arthritis (RA) is a systemic autoimmune disorder that affects middleaged females more than males. There is a genetic predisposition. It usually
presents as a polyarthritis, synovitis, and erosion of the joint surface. Some of
the most characteristic lesions of RA are ulnar deviation, bouttonniere deformity,
swan neck deformity, and z-thumb deformity. You can often also see a
rheumatoid nodule around the elbow, or over other bony prominences.
RA often occurs after an infection with EBV, CMV, parvo, or rubella. T cells
interact with self-antigen and deposit immune complexes in the small vessels in
the joint (synovium) that causes chronic synovitis that is perpetuated by TNFalpha. Long-term effects are joint destruction.
RA can be differentiated from osteoarthritis by the way the symptoms present:
typically RA is worst in the morning, before the patient gets moving. In contrast,
osteoarthritis, which is a disease of wear and tear of the joint, usually gets worse
after exercise.
Know how to diagnose and treat RA (rheumatoid factor, radiography, etc to
diagnose, and treatment is with anti-inflammatory agents, DMARDS, anti-TNF
antibodies, physical therapy, and last resort joint replacement).