AUTOIMMUN PRECIPITATIN MECHANISM HYPERS MEDIATOR PATHOGENESIS DIFFERENTIALS TREATMENT

E DISEASE G FACTORS ENSITIV

ITY
Ankylosing HLA-B27
Spondylitis Class I gene

Rheumatoid Women 30-50 yo Rh Ath antigen causes inflammation Type 3 DR4 Inflammation of small joints Detection of rheumatoid Etanercept +
arthritis Etiology of joints T cells, Hands and feet factors in serum Methotrexate to
unknown Inflammation leads to infiltration of plasma cells, Pleuritis Ab (IgM) against Fc reduce joint
T cells, plasma cells, macrophages macrophages Pericarditis fragment of IgG inflammation in
and inflammatory cytokines Inflammator persistent RA
TNF-α, IL-1, IL-8 cytokines
Causes swelling and inflammation Infliximab and
of synovial membrane adalimumab 
monoclonal Ab
Immune complexes activate
complement cause tissue damage Aspirin
NSAIDs
Immunosuppresive
drugs
Corticosteroids

Myasthenia Etiology Antibodies to acetylcholine Type 2b Antibodies Severe muscle weakness that Positive serology for Corticosteroids
Gravis unknown receptors of neuromuscular against ACh increases during periods of activity anti-AChReceptor Azathroprine
Genetic junctions formed that block the receptors and improves after periods of rest Cyclosporine
predisposition signal of ACh. Double vision Botulinism IV Ig
Dysphagia Cranial nerve Plasmapheresis
Receptors are internalized and Difficulty chewing compression
degraded, resulting in muscle Dyspnea  Respiratory failure Drug induced
weakness myasthenia like
syndrome
Mitochondrial
cyopathy/myopathy
Rheumatic Infection with Molecular mimicry Type 2 Th1 and 1)Polyarthritis Aschoff’s nodes in RHD Antibiotics for S.
fever Streptococcus Th17 for 2)Carditis  Loose pyogenes if
pyogenes 3-5 Cross reaction of Protein M from carditis 3)Erythema marginatum granulomas with ongoing infection
days prior S. pyogenes with glycoproteins from 4)Chorea central fibrinoid
Pharyngitis or myocardial cells Antibodies 5)Subcutaneous nodules necrosis Aspirin/naproxen
“strep throat” vs. Protein M Heart failure drugs
Protein M binds to collagen of heart antigen for If valvulitis is present, permanent JONES CRITERIA  ACEi
tissue and results in fibrous fever damage may be present 1)  Diuretics
pericarditis and interstitial granules  Mitral valvulitis Avoid surgery
with Aschoff’s nodes Sydenham’s chorea during acute phase
of carditis

Insulin Genetic -Antigen – islet cell enzyme, Type 4 DR3DR4 Diabetic ketoacidosis Type 2 DM: IM Insulin
Dependent predisposition glutamic acid decarboxylase Weight loss -Hyperosmolar states
Diabetes Polydipsia more likely than DKA Short Acting for
Mellitus Coxsackievirus -Immune complexes instruct Polyuria -Weight gain rather than post/preprandial
(Type I) B4 inflammatory destruction of insulin loss
producing β cells of the pancreas IV Insulin and KCl
or KCO3 for DKA
hyperglycemia is under the control
of both Th1 and Th2 cells and their
respective cytokines
Multiple Hepatitis B 1 Autoreactive T cells and activated Type 4 DR2 20-40yo, lifelong MRI: beta-interferon,
Sclerosis macrophages cause delineation of Visual disturbance – eg. loss of Multiple focal glatiramer,
white matter central vision and pupillary light demyelination with natalizumab,
reflex asymmetric mitoxantrone
Optic neuritis periventricular plaques
Urinary retention
One eye blindness CSF:
Muscle fatigue ^IgG in CSF
Sporadic muscle weakness Oligoclonal bands on
electrophoresis
 Mononuclear
pleocytosis

Two distinct episodes of

focal neurological
deficits

Positive Babinski sign;

MLF syndrome
Systemic Lupus -Genetic HLA Formation of antinuclear antibodies Type 3 HLA-B8 Skin Malar “butterfly” rash/ CBCPancytopenia Aspirin
Erythematosus predisposition (ANA) to host double stranded -DR2 erythema; exacerbated by sunlight ^ Serum creatinine, NSAIDs
DNA, histones, RNA or nucleolar -DR3 hematuria Corticosteroids
-Inherited C2, C4 antigens Blood  Pancytopenia 
and C1q IgG mediated autoantibodies opsonize RBC, WBC ANA
deficiency C2 and C4 deficiency prevent Immune and platelets Smith antigen (double
removal of immune complex; C1q complexes stranded DNA antigen)
-Ultraviolet Light prevents apoptosis of dead cells Joints Arthritis nonerosive Anti-dsDNA
-Drug induced D4  Drug synovitis with little deformity vs Antiphospholipid
hydralazine UV light causes immunogenic DNA induced SLE erosive synovitis of RA antibodies
procainamide change and localized inflammation Lupus anticoagulant
isoniazid from keratocyte cytokine release  CNS Neuropsychiatric symptoms IgG/M cardiolipin
penicillamine SLE flares in the skin  Cerebritis, Psychosis, Seizures anti-β2 glycoprotein
 SYPHILIS FALSE
-Viral triggers Flares during menses and pregnancy Splenomegaly POSITIVE
EBV and males with Klinefelter’s XXY  Capsular thickening and follicular SSA/SSB  found in
HIV hyperplasia Sjogren’s Syndrome
Drugs cause SLE like response that Concentric intimal and smooth
go away when drug is withdrawn muscle hyperplasia  “Onion-skin” Immunoflourescence
lesions Not specific but hints
Infection causes molecular mimicry to SLE
(antigen from virus binds to antigen Lungs
from host DNA, sensitizing immune Pleuritis Histology 
system to host) Pleural effusions IgG/immune complex
 Chronic interstitial fibrosis deposits in kidneys and
Homogenous nuclei of damaged Secondary pulmonary hypertension skin
cells with ANA binding to nuclei 
LE bodies Kidneys Malar rash also found in
 I – Minimal mesangial scleroderma or
II – Mesangial proliferative dermatomyositis
 Mesangial proliferation without
complex deposition DISCOID LUPUS
 Granular mesangial deposits
ERYTHEMATOSUS
III – Focal proliferative
 Segmented/global lesions Skin plaques
 Crescent formation Edema
 Fibrinoid necrosis Scaliness
 Endothelial/mesangial proliferation
 <50% glomerular involvement Follicular plugging
IV – Diffuse proliferative Elevated
 Focal lesions erythematous border
 Endothelial, mesangial and epithelial Double stranded
proliferation
 Cellular crescents filling the space DNA antibodies rarely
 >50% glomerular involvement present
V – Membranous
glomerulonephritis SUBACUTE
 Diffuse thickening of capillary walls CUTANEOUS LE
 Proteinuria
 Nephrotic syndrome Widespread and
 Focal/ diffuse lupus nephritis superficial nonscarring
 “Wire loop” lesions of capillary wall in rash
focal and diffuse proliferative
 Subendothelial deposits more likely in Type
3 and 4
Interstitial and tubule changes
Sjogren Isolated or Immunologically mediated HLA B8 Dry eyes (keratoconjunctivitis sicca) Lip biopsy is essential Corticosteroids
Syndrome secondary destruction by of salivary and DR3 Dry mouth (xerostomia) Aspirin
association with lacrimal glands, causing dry mouth DRW52 Acini atrophy SLE NSAIDs
another and dry eyes DQA1/B1 Fibrosis and hyalinization Polymyositis
autoimmune Dysphagia Vasculitis
disease SSA (Ro) Angular stomatitis
 Lymphocytic infiltration of CD4, SSB (La) Mixed connective tissue
Viral infection of Th cells and B cells (perivascular High risk of B-cell lymphoma disease
salivary glands and periductal) IgG and Marginal zone lymphoma Thyroidosis
Hepatitis C Fibrosis of glands rheumatoid
Epstein Barr factor ^SSA Extraglandular manifestation
 High SSA levels  early disease CD4 Synovitis
onset, cutaneous vasculitis, nephritis T-helper Diffuse pulmonary fibrosis
B cells Peripheral neuropathy
Renal tubular acidosis
 Impaired hydrogen transport or bicarbonate
reabsorption
Uricosuria
Graves’ Disease 40-60 yo Antibodies form to TSH receptors Type IIb HLA-DR3 Symptoms mimic hyperthyroidism Thyroid function Radioiodine
Women > men that bind to and activate TSH DRB1 Goiter  T3 and T4 high; Antithyroid drugs
receptors. Ophthalmopathy serum TSH low  Thionamine
High doses of Stimulates hormone synthesis from IgG Smooth, dry skin  T3 toxicosis  T3  Prophylthiour
iodine thyroid cell Anxiety > T4 with low TSH acil
Recent childbirth Triggers unregulated overproduction Insomnia  Methimazole
Smoking of thyroid hormones  symptoms of Weight loss TSH receptor binding Surgery
Infection hyperthyroidism antibodies
Physical stress Diplopia
Genetic Chemosis Thyroiditis
predisposition Menstrual irregularity Autonomously
functioning nodle
Psychosis
Tachyarrhythmia  cardiac failure
Pemphigus Drugs IgG antibodies formed against Type 2 DR4 Oral recurrent vesicobullous ulcers Perilesional biopsy used 1st line:
vulgaris Penicillamine Desmoglein 3 of the oral mucosa 2-6 mo desmoglein 3 and to confirm Azathioprine and
ACE inhibitors (Or 1 and 3 in severe cases) causing Antibody desmoglein 1 antibodies are present, mycophenolate
acantholysis in the stratum mediated cutaneous vesicobullous ulcers occur Apthous stomatitis mofetil
Diet spinosum. (Type 2) Lichenplanus
Garlic Oral recurrent vesicobullous ulcers Oral candiasis 2nd line:
Spicy food appear  Schiff test Rituximab is
Behcet’s disease extremely
 Virus infection 2-6 months after oral desmoglein Blisters are thin roofed and liable to  Oral and genital effective in
1 and 3, oral and cutaneous ulcers bursting and haemorrhage  Painful apthae recalcitrant
appear ulceration Bullous pemphigus pemphigus
 Tension blisters on
extremities
Impetigo
 Bacterial infection,
honey crusted
Guillain Barre -infection of -Acute post-infective polyneuritis, TYPE II -Rapidly progressing ascending -Spread is rapid and Immunoglobulin
Syndrome Campylobacter acute paralysis (Cytotoxi paralysis ascending upwards from transfer (IV)
jejuni, respiratory -Antibodies formed against myelin c) 1) back and limb pain lower limbs
tract infections, -Myelin on peripheral nerves 2)increasing weakness -Chronic Inflammatory Plasmapheresis
HIV infection, degraded – demyelinating 3)ascending weakness and paralysis Demyelinating
mononucleosis polyneuropathy Polyradiculoneuropathy
from Epstein-Barr Demyelinating polyneuropathy (CIPD)
virus, Paralysis can spread to respiratory Longer lasting, chronic
Cytomegalovirus nerves  need ventilator illness similar to GB

Chronic Inflammatory Demyelinating

Polyradiculoneuropathy (CIDP)

Myocarditis Cocksackie B3

Autoimmune WARM IgG antibodies coat RBC membrane Type 2 IgG, active at Spleen Coomb’s test  IgG Steroids
haemolytic Idiopathic once active and lyse the RBC 37oC Extravascularly positive with C3 Immunosuppressio
anemia Non-Hodgkin’s membrane Mid jaundice n
Hodgkin’s RBC become more spherical Splenomegaly Blood film Splenectomy
Rheumatoid Acrocyanosis toes, fingers, ears Large reticulocytes Cyclophosphamide
arthritis Fix complement intravascular Spherocytes Cyclosporin
SLE haemolysis Cell fragments
Drugs
penicillin
cephalosporin Opsonins extravascular hemolysis 1. Removing drug
Fanconi’s within phagocytes usage/ treat
syndrome underlying cause
Tends to remit and relapse 2. Corticosteroids
1mg/day
ITP + WAHA Evan’s Syndrome complement
fixed RBC respond
Secondary to SLE coated with poorly
both IgG and complement (C3d);
uptake occurs in reticuloendothelial 3. Monoclonal
system antibody eg. Anti-
CD20 rituximab
used w/
corticosteroids

4. Splenectomy

Immunosuppressio
n; anti-CD52,
azathioprine,
cyclophosphamide
, chlorambucil
Folic acid
supplements

5. RBC transfusion
COLD Cold agglutin syndrome appears IgM, active Intravascular occlusion IgGRh antigen Immunosuppressio
Mycoplasma after Mycoplasma infection, at 4oC Often occurs in peripheral vessels n
infection mononucleosis (EBV) or LPD such as fingers and toes Coomb’s test  IgG Chlorambucil
Waldenstrom’s negative, with only C3 Alkylating agents
macroglobulinemi AGGLUTININ: Chlorambucil
a Pallor
Cyanosis
 Raynaud’s phenomenon recurrent Purine
vasospasm in cold nucleotide
analogues
IgM binds RBC fixes complement
rapidly and releases when warmed Anti CD20 –
before hemolysis occurs rituximab
Causes sublytic C3b to be
deposited Splenectomy and
RBC sequestered in spleen and corticosteroids DO
liver by phagocytes NOT work
Extravascular hemolysis

HEMOLYSIN:
Hemoglobinuria
Paroxysmal Cold Intravascular hemolysis
Haemoglobinuria:
SLE Donath Landsteiner antibody - IgG
Measles/mump specific for P antigen
CLL IgG binds to P antigen on RBC
Ulcerative coli surface complement cascade
Ovarian operates at 37oC and causes lysis of
teratoma RBC FATAL intravascular
Methyldopa hemolysis
Immune Both childhood Deficiency of platelets due to formation Type 2 IgG vs Spleen: DECREASED platelet count Glucocorticoids:
Thrombocytic and adult of antibody IgG against IIIa/IIb or Ib/IX (Cytolyti IIIa/IIb Scattered megakaryocytes from (<150x10(9)/L)
Purpura Acute c) Or extramedullary hematopoesis driven by IV immunoglobulins;
Persistent Resolves spontaneously in children Ib/IX increase in thrombopoeitin PT normal
Chronic without treatment PTT normal Splenectomy; is
Marrow: major site of
Chronic: Splenic destruction; splenomegaly is -INCREASED megakaryocytes Responds to removal of
Under 40 yo rare glucocorticoids opsonized platelets
 Primary – Solitary thrombocytopenia Blood film: and a source of
idiopathic Skin bruising -Megathrombocytes/ giant platelets autoantibodies
Mucous membrane bleeding from increased thrombocytosis
 Secondary – Petechiae  if confluent leads to -Schistocytes increased risk of
SLE, B-cell ecchymoses infection and sepsis
neoplasms, CLL Melena, Hematuria Splenic atrophy/destruction
Solitary thrombocytopenia Thrombopoietin
Acute: Petechiae & ecchymoses receptor agonists
Post viral; Mucous membrane bleed
Epstein-Barr, Melena Rituximab; anti-
HIV, dengue Haematuria CD20 monoclonal
-Resolves antibody
spontaneously in
6 months

Autoimmune High dose chronic Autoimmune destruction of all Type 2 IgG Adrenal failure Sheehan’s syndrome Daily flucortisone
Adrenalitis steroids layers of the adrenal gland antibodies Addison’s disease Adrenal insufficiency Methotrexate
Surgery against  Destruction of all 3 layers of Tuberculous adrenalitis
Tuberculosis Antibodies against CYP17 and CYP17 and adrenal cortices
HIV CYP21A2 CYP21A2  Decrease in aldosterone, cortisol,
steroids
Formation of 21-hydroxylase
antibodies leasing to decrease in Fatigue, worsens with stress
response to ACTH Weight loss
Anorexia
Nausea

Hypotension
 Decrease in aldosterone
Hyperpigmentation
 Melanocyte stimulation from
increase in ACTH
Hypoglycaemia
 Decrease in cortisol mediated
glucogenesis
Pernicious Genetic Chronic atrophic gastritis from Type 2 Either B12 deficiency CBC Folic acid and
Anemia Autoimmune autoimmune response - a/b to mediated by Megaloblastic anemia HIGH reticulocytes cobalamin
polyendocrine Antibodies formed against intrinsic intrinsic antibodies to Jaundice HIGH hematocrit supplements
syndrome factor or its binding receptor, factor, intrinsic
preventing transport of B12 factor (type Moderate-severe megaloblastic HIGH homocysteine
2) anemia HIGH methylmalonic acid
Type 1 antibody – blocks binding of vit Type 4 Or
B to intrinsic factor - reaction T cells vs Anisocytosis, poikilocytosis LFT, TFT
against gastric Macro-ovulocytes
Type 2 – prevents binding of intrinsic gastric parietal cells Reticulocytes HIGH anti-intrinsic factor
factor-B12 complex to ileal receptor for parietal antibodies
absorption cells Nucleated RBC
Type 3 – recognize αβsubunits on Leukopenia with hypersegmented Dietary insufficiency
gastric proton pump H. Pylori infection
granulocytes (>5 lobes rather than 3-
4 because of nuclear to cytoplasmic  Atropy of fundic
Autoimmune thyroiditis, adrenalinitis, glands
asynchrony)
diabetes Gastric carcinoma
Large promegablasts
Giant metamyelocytes and band
forms instead of granulocytes

Pancytopenia from RBC DNA lysis

Celiac Disease
High dose chronic
steroids

Autoimmune INF-gamma produced by CD4+ and HLA- Clusters in plasma cells in portal tract Prednisone +
hepatitis CD8+ T cells triggered by drugs or DR3 interface and lobules Azathioprine
viral infection Fulminant hepatitis

Type 1 Antinuclear Ab
 Anti smooth muscle
Anti actin

Type 2
Anti-liver kidney microsome-1
Anti liver cytosol

Primary Biliary More often in Non-suppurative inflammatory HLA-B8 Portal inflammation Elevated serum ALP
Cirrhosis women destruction of medium sized -DR2 Scarring Elevated Total
intrahepatic bile ducts -DR3 Liver cirrhosis and failure Cholesterol
Hepatic encephalopathy Elevated GGT
Small duct biliary fibrosis and
cirrhosis Fatigue Hyperbilirubinemia
Portal tracts infiltrated by dense Pruritus Antimitochondrial
accumulation of leukocytes Eyelid xanthelasmas antibodies
Noncaseating granulomatous Hyperpigmentation from melanin
inflammation deposition
Hepatosplenomegaly
Secondary Not autoimmune, comes from end
Biliary stage liver due to obstruction of the
Cirrhosis extrahepatic biliary tree
Autoimmune Presence of other Antibodies to gastric parietal cells Type 2 Antibody and Parietal and gastric atrophy of the Parietal and gastric Immunosuppressio
Gastritis autoimmune and intrinsic factor T cell BODY of stomach antibodies n
disorders Destruction of gastric parietal cells mediated Lymphocytic and macrophage v Serum pepsinogen I allows gastric
leading to no acid secretion  infiltrate  Due to cell stem cells to
increase in gastritis v acid production  destruction of destruction reproduce and
Hypergastrinemia gastric cells Antral endocrine cell repopulate
^ Gastrin production hyperplasia
CD4 T cells vs parietal cells Vit B12 deficiency
Gastric atrophy
Unlike H. Pylori, immune gastritis Pernicious anemia Hashimoto thyroiditis
spares the antrum  Atrophic glossitis Type 1 DM
 Epithelial megablastosis Addison’s disease
 Causes hyperplasia of antral gastrin  Malabsorptive diarrhea Grave’s disease
producing G-cells  Demyelination and peripheral Vitiligo
neuropathy, psychosis
Adenocarcinoma
Carcinoid tumor

Inflammatory Genetics Severe ulcerating inflammation NOD-2 Involves any part of the GIT eg. Barium enema showing Prednisone
Bowel Disease  NOD2 – RESTRICTED TO COLON Th2/ IL-23 Apthous stomatitis fistulas and abscesses Sulfasalazine
activates Extends only into mucosa and Anti-TNF Deep transverse fissures and Azathioprine
Crohn’s NK-kB, submucosa ulceration Infliximab
prevent Linear stellate ulcers
Ulcerative excessive Skip lesions
Colitis microbe Creeping fat
activation Fistulas likely
Th2 or IL-23
Systemic:
erythema nodosum
uveitis
arthritis
kidney stones
NOD2 Regional enteritis bc of frequent Colicky abdo pain Sacroilitis Mesalamine
ATG16L1 ileal involvement Bloody diarrhea with mucous Large joint arthritis enema
IRGM Transmural Psuedopolyps IV steroids
Defect in Extends throughout GIT Crypt abscesses Barium: Cyclosporine
intestinal Psuedopolyps Loss of haustra
epithelial tight Friable mucosal patches Shortening of bowel
juntion ”Lead pipe” appearance

HIGH RISK OF COLON

CANCER

Hashimoto Hypothyroidism
Thyroiditis Fatigue
 Weight gain
Constipation
Dry skin
Autoimmune Mutation in AIRE AIRE mutation stimulates
Polyendocrinop expression of peripheral self
athy antigens in thymus, deleting
immature T cells
Reiter’s Chlamydia Large joint arthritis
Syndrome trachomatis (D- Sacroiliac
K) and Shigella Knee
COINFECTION
Conjunctivitis
Urethritis
“Can’t see, can’t pee, can’t bend my
knee!”
Allergic Rabies vaccine Foreign myelin cross reacts with Type 4 T helper
encephalitis from rabbit brains human myelin  molecular Macrophages
injected into mimicry
humans Cerebral inflammation when
immune response is mounted against
human myelin
Erythroblastosis Type 2
fetalis

HLA genes encode Class I or Class II MHC proteins that present autoantigens with greater efficacy than the MHC genes that are normal.
Hypersensitivity Reactions

Hypersensitivity Reaction
Pathophysiology Clinical Examples
Type

 Anaphylaxis
o allergens
 bee sting
 food (e.g., peanuts)
 drugs
 Immediate
Type I (anaphylactic and  Asthma
 Antigens cross-link IgE antibodies triggering
atopic) o allergens
o vasoactive amine release (e.g., histamine)
 inhaled materials
 Allergic rhinitis
o allergens
 animals
 trees

 Antibodies are directed against cell-surface antigens resulting in  Autoimmune hemolytic anemia
o opsonization o antigen
Type II (cytotoxic) o complement activation  erythrocyte membrane proteins
o neutrophil and macrophage recruiting  Acute rheumatic fever
o NK cell killing o antigen
o impairment of cellular function  myocardial antigens via cross-reacting with S.
pyogenes M protein
 Goodpasture syndrome
o antigen
 type IV collagen
 Immune thrombocytopenic purpura
o antigen
 platelet membrane proteins
 Myasthenia gravis
o antigen
 acetylcholine receptors
 Graves' disease
o antigen
 TSH receptors
 Erythroblastosis fetalis
o antigen
 Rh antigen
 Pemphigus vulgaris
o antigen
 desmosomes
  Serum sickness
 Arthus reaction
 IgG antibodies complexes withself or foreign antigens resulting in
Type III (immune-complex)  Systemic lupus erythematosis
o complement activation
 Polyarteritis nodosa
 Poststreptococcal glomerulonephritis

 CD8+ T-cells directly destroy the target cell

 Type I diabetes meilltus
 Pre-sensitized CD4+ helper T-cell releases cytokines when re-exposed
Type IV (cell mediated)  Contact dermatitis
to the offending material
 Tuberculin test
 Notice this does NOT involve antibodies

 