MOD #102
Thurs, 05/15/03, 1pm
Dr. Putthoff
J. Uxer for Prateek Chaudhary
Page 1 of 8
I.
II.
III.
Diseases of Immunity
Introduction
A. Miscellaneous
 Note on the calendar that solo professor CILs are 2 hours long and joint
professor CILs are 3 hours long.
 Next, we got to sit through an extensive diatribe concerning cheating on
quizzes and the amount of e-mail Dr. Putthoff has received about it. Again,
the class was reamed for things that the majority are not participating in.
 Dr. Putthoff reminds us of the big picture and concepts in lectures. Keep the
disease generation process in mind—don’t just focus on 1 word in the
scenario
 ~30% of diseases present with the common, classic signs and symptoms
listed in textbooks. So, understand the diagnostic reasoning. Novices go
step-by-step; experts can leap over some of the steps. This may involve
pattern recognition.
B. For this exam
 Look at the tables in the power points and refer to the book for these.
Dr. P said he won’t ask it on an exam if it’s not in the text.
 1. Robbins Pathologic Basis of Disease, 6th Ed., Chapter 7, Diseases of
Immunity
 2. McKenna, et al, Handbook of Clinical Pathology, 2nd. Ed.
o Chapter 29, Autoimmune Diseases
o Chapter 30, Immunodeficiency Diseases
General features of the Immune System
 Review material*
 Cells of the Immune system
Hypersensitivity
 Learn to distinguish between Type I, II, III, & IV hypersensitivities
 Table 7-2**, pg. 196
A. Type I - anaphylactic type
 Can be defined as a rapidly developing immunologic reaction occurring
within minutes after the combination of an antigen with antibody bound to
mast cells or basophils in individuals previously sensitized to the antigen
 Fig. 7-9, pg. 197*
 May be a local or systemic phenomenon
 The role of basophils and mast cells
 In humans, type I reactions are mediated by IgE antibodies
Primary mediators
Secondary mediators
Fig 710, p. 198
 Summary of the action of mast cell mediators in type I hypersensitivity
o Cellular infiltration
o Vasoactive
o Smooth muscle spasm
 Table 7-3 p. 199**
MOD #102
Thurs, 05/15/03, 1pm
Dr. Putthoff
J. Uxer for Prateek Chaudhary
Page 2 of 8
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The thought is that histamine is a major factor in Type I reactions.
Histamine causes vasodilation, increased vascular permeability leading to
edema, and smooth muscle spasm.
Learning that leukotrienes are just as important in Type I reactions as
histamine is.
Do people die of asthma? Yes. (also die from epilepsy, typically in their
sleep)
Histamine:
stimulate kinins, C3a
pg. 72
Note Fig. 3-18, pg. 71
proteoglycans
B. Type II - cytotoxic type
 Mediated by antibodies directed toward antigens present on the surface of
cells or other tissue components
o Complement –dependent reactions
o Antibody-dependent cell mediated cytotoxicity
o Antibody mediated cellular dysfunction
 Figures are in the next 3 slides but were not discussed in class.
C. Type III - Immune complex disease
 Mysthenia gravis
 Old term = serum sickness
 is induced by antigen-antibody complexes that produce tissue damage as a
result of their capacity to activate the complement system
 Two types of antigens
o exogenous*
o endogenous**
 Table 7-5, p. 201*
 Systemic immune complex dz – 3 phase
 Formation of Ag-Aby complexes in the circulation
 Deposition of the immune complexes in various tissues, thus
MOD #102
Thurs, 05/15/03, 1pm
Dr. Putthoff
J. Uxer for Prateek Chaudhary
Page 3 of 8
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Initiation of an inflammatory reaction in dispersed sites throughout the body
Again, more slides of pictures that were not discussed.
The ultimate result is vascular injury
o Blood vessels = vasculitis
o Glomeruli = glomerulonephritis
o Joint surfaces = arthritis
o 2 things can happen: the intima and smooth muscle are left intact and
you see inflammatory cells streaming through as below. Or, the intima
and smooth muscle can be destroyed and there is a fibrinoid
appearance—this is the hallmark of immune injury.
 Arthus reaction – [def] a local area of tissue necrosis resulting from acute
immune complex vasculitis, typically in the skin
D. Type IV – cell mediated (delayed)
hypersensitivity**
 Granulomas are characteristic of Type IV hypersensitivity.
 They must meet 3 criteria:
1. space occupying
2. made of epitheliod cells, histioid cells—activated macrophages
3. not around blood vessels (if they are, it’s vascultis)
 You don’t have to see giant cells
 Mycobacteria infection (TB)—see caeseating or necrotizing granuloma
 Sarcoidosis—no central necrosis or caeseation
 Fungi infection—angioinvasive fungi—opportunistic. Aspergillus
 The cell mediated type of hypersensitivity is initiated by specifically
sensitized T lymphocytes. It includes the classic delayed-type
hypersensitivity reactions initiated by CD4 T cells and direct cell
cytotoxicity mediated by CD8 T cells. It is the principal pattern of
immunologic response not only to a variety of intracelluar microbiologic
agents, particularly Mycobacterium tuberculosis, but also to many viruses,
fungi, protozoa and parasites. So-called contact skin sensitivity to chemical
agents and graft rejection are other instances of cell-mediated reactions.
 Delayed-type (classic example) – tuberculin reaction
 granulomatous inflammation is often characteristic of Type IV
hypersensitivity—look at the power points for the histo slide
 T cell-mediated cytotoxicity
 CTLs (cytotoxic T lymphocytes) have a variety of roles
KNOW WHAT TYPE OF HYPERSENSITIVITY HEMOLYTIC ANEMIA
REPRESENTS!!! (1st subtype [complement-dependent] of Type II)
IV. Transplant rejection
 Transplants are done at most major referral hospitals
 Graft vs Host reaction
o In bone marrow transplantations, 1st the marrow is irradiated to kill the
neoplastic cells.
o Next, bone marrow from someone else is injected into the patient (note that
there’s a HLA match with this)
MOD #102
Thurs, 05/15/03, 1pm
Dr. Putthoff
J. Uxer for Prateek Chaudhary
Page 4 of 8
o The bone marrow = the graft. It can react against the host.
Appears to involve several of the hypersensitivity reactions
Rejection is a complex process in which both cell mediated immunity and
circulating antibodies play a role
 T cell mediated reactions
 Antibody mediated reactions
 Morphology—Know what these are and how they’re different!
o hyperacute
o acute
o chronic
 Note schematics and photomicrographs in the text p. 208-209
 Look at methods of increasing graft survival, transplantation of other solid
organs, and transplantation of hematopoietic cells.
Autoimmune Diseases
 Collagen vascular disease is another name for autoimmune disease
 Go through the mechanisms of autoimmune diseases. Pick out the major
elements—the italicized and/or bolded things.
 Know the criteria for being considered an autoimmune disease
 Only a few diseases fit this criteria; systemic lupus erythematosus is one that
does.
 There is an arrangement of antinuclear antibodies (DNA, RNA, histones, illicit
antibody formations) in all autoimmune diseases.
 As you age, you increase the number of antibiodies titered from your body, yet
you’re perfectly healthy.
 [def] pathologic immunity (3 criteria)
 Table 7-6**
 The autoimmune diseases form a spectrum
o autoantibodies specifically directed against B cells in the pancreatic islets
(ID DM)
o antibodies directed against components of glomerular and alveolar septal
basement membranes cause injury and disease in those specific organs
o a diversity of antibodies directed against DNA, platelets, red cells and
protein-phospholipid complexes resulting in lesions ubiquitous throughout
the body (SLE)
 Immunologic tolerance
o Central tolerance
o Peripheral tolerance
 Mechanisms of autoimmune diseases
o
-it is clear that there are a number of ways by which tolerance can be
bypassed, thus terminating a previously unresponsive state to autoantigens
o pp. 214 – 215, esp. genetic factors
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V.
A. Systemic lupus erythematosus
MOD #102
Thurs, 05/15/03, 1pm
Dr. Putthoff
J. Uxer for Prateek Chaudhary
Page 5 of 8
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The classic prototype of the multisystem disease of autoimmune origin,
characterized by a bewildering array of autoantibodies, particularly
antinuclear antibodies (ANAs)
Acute or insidious in its onset, it is a chronic, remitting and relapsing, often
febrile illness characterized principally by injury to the skin, joints, kidney
and serosal membranes. However, virtually any and possibly every other
organ in the body may also be affected
Table 7-7, pg. 217*
Prevalence
gender predilection
ethnic predilection
Etiology and pathogenesis
– ANAs can be grouped into (4) categories*
– Know the patterns of nuclear immunofluorescence
– Which antibodies (2) are virtually diagnostic of SLE?
– See Table 7-8** and group by antibody system
Note what the latest experimental evidence says about
o genetic factors
o nongenetic factors
o immunologic factors
Presentation: melar rash, sericitis—inflammation or transudate, pleurities,
pericarditis, joint effusions, endocarditis—very common
Morphology
– Table 7-9, pg. 220*
– Summary of disease, pg. 220*
– kidney
– skin
– joints
– CNS
– pericarditis and other serosal cavities
– heart, endocarditis, etc.—can see Lipman Sack’s endocarditis plateletfibrin deposits on the heart valves. These are not infectious.
 Infectious endocarditis is seen in IV drug users and
immunocompromised patients.
 Staff endocarditis is necrotizing and eats through the heart valves.
– spleen
– lungs
– other organs and tissues
– ?: “lupus anticoagulant” (referred to by Dr. Wasson) These cause DVT
and thrombosis in other parts of the body. This is counterintuitive to
what you’d expect.
Clinical course (what are the most common causes of death due to
SLE?) Important to differentiate between the types of lupus.
Chronic discoid lupus erythematosus—primarily involves skin
MOD #102
Thurs, 05/15/03, 1pm
Dr. Putthoff
J. Uxer for Prateek Chaudhary
Page 6 of 8
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Subacute cutaneous LE
Drug-induced LE—primarily has skin manifestations, but does not have the
entire spectrum that SLE has
 Know the antibodies. They will be on the exam.
B. Sjogren Syndrome (60-90 RNP; either RNP)
 This is a clinicopathologic entity characterized by dry eyes
(keratoconjunctivitis sicca) and dry mouth (xerostomia) resulting from
immunologically mediated destruction of the lacrimal and salivary glands
o Xerostomia predisposes a person to infection because enzymes and
secretory IgA are in the mouth when it is wet.
o Woldyers ring—at the back of the throat including the palatine tonsils.
Leukemias can present here, and only here.
 Sjogren Syndrome is not well understood.
 Etiology and pathogensis
o lymphocytic infiltrates
o Genetic factors
o T cell involvement?
o @ w/ viruses, HIV, HTLV-1?
 T-cell injury recently associated with HIV and HTLV-1 (note that
these are not the same virus. HIV 1, HIV 2 lead to AIDS, HTLV-1
thru 3 lead to T-cell lymphomas)
 Refer back to Table 7-8, pg. 218* for the antibody patterns and which
antibodies are most common
 Clinical manifestations & laboratory manifestations. It’s a clinical
pathologic presentation.
o See lacrimal swelling.
o Oraniod configuration—epitheliod cells with inflammatory cells
infiltrating major lacrimal glands (sublingual, submandibular, parotid).
Can also affect minor lacrimal glands in the lips and oral cavity. Many
times a lip biopsy is done for confirmation. This is not solely indicative
of Sjogren’s.
 How do you diagnose Sjogren Syndrome? (60-90 RNP; either RNP)
C. (Progressive) Systemic sclerosis (scleroderma) (DNA topo I 28-70)
 Characterized by excessive fibrosis throughout the body
 Think of it as diffuse systemic scarring. Look at the pictures in the book for
a better idea. These patients can even have trouble opening their mouths
due to the contractures.
 Diffuse
 Localized—morphia
 CREST syndrome—calcinosis, Raynaud’s phenomena, esophageal
problems, sclerodactyly, and telangiectasia
 Etiology and pathogenesis
MOD #102
Thurs, 05/15/03, 1pm
Dr. Putthoff
J. Uxer for Prateek Chaudhary
Page 7 of 8
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D.
E.
F.
G.
microvascular disease is consistently present early in the course of SS (both
immune and non-immune)—CREST syndrome is more limited with a better
prognostic (centromeric proteins = 90)
 Sometimes the small blood vessels are obliterated.
 Table 7-8, pg. 218*
 Morphology/organ involvement
o Skin—atrophic epidermis, expansion of dermis, destruction of sebaceous
glands leading to alopecia.
o alimentary tract
o musculoskeletal system
o kidneys
o lungs
o Heart
 Clinical course
Inflammatory myopathies (histadyl-t-RNA synthetase = 25)
 Uncommon
 Favorite question on national boards
 Inflammatory myopathies comprise an uncommon, heterogeneous group of
disorders characterized by immunologically-mediated injury and
inflammation of mainly the skeletal muscles
 Dermatomyositis—affects proximal muscles, have a skin rash, heliotroph
(blue tint) on eyelids, affects bilaterally
 Polymyositis—proximal muscles; bilaterally affects patient
 Inclusion-body myositis—1st described in the last 10 years; asymmetrical
distribution; affects distal muscles
 Know the etiology and pathogenesis for each. Also note the differences
in age distributions
Mixed connective tissue disease
 Note especially ANA patterns/titers
 Clinical manifestation
 Diagnosis
 Treatment—steroids, radiation treatment
 Shows different ANA patterns. Note these in the text.
 Serologically high titers to ribonucleoproteins
Polyarteritis Nodosa and other vasulitides
 Not very common
 Involve kidneys and all other blood vessels
 Primarily involves medium caliber arteries (past board question)
 Inflammatory cells in blood vessel walls
 May see fibrinoid.
Summary
 Immunologic deficiency syndromes be able to [def], describe, know major
manifestations and unique (differentiating) features
MOD #102
Thurs, 05/15/03, 1pm
Dr. Putthoff
J. Uxer for Prateek Chaudhary
Page 8 of 8
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Tell what immunodeficiency you have in each of the following diseases.
Know the MAJOR clinical manifestation.
 Primary immunodeficiencies
– X-linked agammaglobulinemia of Bruton
– Common variable immunodeficiency
– Isolated IgA deficiency—most common
– Hyper IgM syndrome—associated with lymphoma
– DiGeorge Syndrome (Thymic hypoplasia)—very little or no thymus
– SCID—Severe Combined Immunodeficiency Disease
– Immunodeficiency with thrombocytopenia and Eczema (WiskottAldrich Syndrome)
– Genetic deficiencies of the complement system
VI. Acquired Immunodeficiency Syndrome
 This book has the “best discussion of AIDS”
 Every year you hear of extending people’s lives when they have AIDS, so some
docs are calling it a chronic disease. This really only occurs because they
caught the disease early and begin treatment
 Many times we will just see them in the end stages.
 ~40% of the African population is HIV +. This is probably a different strain.
 AIDS is a retroviral disease characterized by profound immunosuppression that
leads to opportunistic infections, secondary neoplasms and neurologic
manifestations
 A modern plague; morbidity and mortality are staggering
 Epidemiology – at least 5 groups of adults in US are considered high-risk
o KNOW THE GROUPS!
o Homosexual/bisexual men are the largest group.
o Those at highest risk are the receptive partner in anal intercourse because
the mucosa is easily torn allowing the virus access to the inside of the body.
o In heath care, it usually occurs with very deep needle sticks.
 3 major routes of transmission
 Etiology
 Know that p24, gp120, and gp41 are used to diagnose AIDS and are capsid
proteins. They are important in the search for vaccines. New vaccines have
tried to make viruses with the antibodies against the capsid proteins. These are
usually attenuated live viruses like polio, but to date this has not worked for
AIDS because you cannot attenuate live HIV.