Hypersensitivity III and IV
Type III β why size decides everything β β β
Immune complexes form in every antibody response β antigen binds antibody, that is the point. So why are they normally harmless and occasionally devastating? The answer is size, and it is the most elegant idea in this unit.
| Small IC | Medium IC | Large IC | |
|---|---|---|---|
| Ratio of Ag to Ab | Ag β« Ab | Suitable; appropriate | Ag > Ab |
| Size | <19S | β19S | >19S |
| Activates complement | β | +++ | +++ |
| How cleared | Filtered by the glomerulus | Deposits in local sites; difficult to remove | Cleared by the phagocyte system |
| Rate of clearance | Slow | Moderate | Fast |
| Degree of damage | β | Causes immune complex disease | β |
Read the bottom row: damage occurs only in the middle column, and it is worth understanding why the two extremes are safe.
Large complexes form when antibody is plentiful. They are big enough for the phagocyte system to see and remove promptly β cleared fast, no damage.
Small complexes form in large antigen excess. They are small enough to pass straight through the glomerulus into the urine, and too small to activate complement β no damage.
Medium complexes are the trap: too small for phagocytes to clear efficiently, too large to filter out β so they circulate, lodge in small vessels, and they activate complement strongly. They are stuck in exactly the place where they can do harm. The danger is not the complex; it is being the wrong size to be removed.
Where they lodge is anatomically predictable, and it explains the clinical picture: the synovium of joints, the glomerular basement membrane of the kidney, and the choroid plexus of the brain β sites where blood is filtered under pressure through small vessels.
- Which size of immune complex causes disease? → Medium, β19S, formed at an appropriate Ag:Ab ratio
- How are large complexes cleared? → Rapidly by the phagocyte system
- How are small complexes cleared? → Filtered by the glomerulus; they do not activate complement
- Why are medium complexes dangerous? → Too small to be phagocytosed, too large to filter β they deposit and activate complement
- Name the three main deposition sites. → Joint synovium, glomerular basement membrane, choroid plexus
How a deposited complex causes injury β β β
| Mediator | Effect |
|---|---|
| C3a, C4a, C5a β anaphylatoxins | Mast cell and basophil degranulation β increased vascular permeability |
| C3a, C5a, C5b67 β chemotactic factors | Recruit neutrophils, which release lytic enzymes |
| C3b | Activates platelets β release histamine β vasodilation, increased permeability, platelet aggregation |
- Soluble antigen stimulates antibody production; immune complexes form.
- Medium-sized complexes deposit in small vessels.
- Deposits activate complement, generating C3a, C5a and C5b67.
- Neutrophils infiltrate and release lytic enzymes; mast cells and basophils degranulate, increasing permeability.
- Platelets aggregate, forming microthrombi.
- The result is oedema, haemorrhage and tissue damage β local or systemic disease.
Note that the antibody itself does almost none of the damage. It deposits, complement amplifies, and neutrophils do the destroying.
- Which complement fragments increase vascular permeability? → The anaphylatoxins C3a, C4a, C5a
- Which recruit neutrophils? → C3a, C5a and C5b67
- What do the recruited neutrophils do? → Release lytic enzymes, damaging tissue
- What causes microthrombi? → C3b activating platelets, which aggregate
Local immune-complex disease β β
| Disease | Detail |
|---|---|
| Arthus reaction (1903) | Experimental local IC disease at a small blood vessel wall. A rabbit repeatedly immunised subcutaneously with horse serum develops oedema, erythema, even necrosis |
| Arthus-like reaction | In humans β repeated injection of insulin in a type 1 diabetic. Localised tissue and vascular damage gives swelling, redness, even necrosis at the injection site |
| Intrapulmonary Arthus-type reactions | Induced by bacterial spores, fungi or dried faecal proteins; complexes deposit on the alveolar wall, causing pneumonitis. Pigeon breeder's lung (dried faecal proteins) Β· Farmer's lung (spores or fungi) |
- What is the Arthus reaction? → Experimental local immune-complex disease at a small vessel wall, from repeated subcutaneous immunisation
- Give a human Arthus-like example. → Repeated insulin injection in a type 1 diabetic
- Name two intrapulmonary Arthus-type diseases. → Pigeon breeder's lung and farmer's lung
Systemic immune-complex disease β β β
| Disease | Antigen and antibody | Where complexes deposit |
|---|---|---|
| Serum sickness | Large amounts of antiserum (anti-tetanus, anti-diphtheria). 1β2 weeks later: fever, weakness, vasculitis | Vessels generally |
| Post-streptococcal glomerulonephritis | 2β3 weeks after haemolytic streptococcal infection: anti-streptococcal antibody + soluble streptococcal antigen | Glomerular basement membrane |
| Rheumatoid arthritis (RA) | Auto-antigen: degenerated IgG. Auto-antibody: anti-IgG = rheumatoid factor (RF), an IgM | Synovium of small joints |
| Systemic lupus erythematosus (SLE) | Auto-antigens: DNA, histones. Auto-antibody: antinuclear antibody (ANA) | Multiple tissues |
Follow the thread. Unit 2 said horse antitoxin has a dual nature: it is a specific antibody and a xenogeneic antigen. Unit 3 said the Fc is removed by pepsin digestion to reduce that immunogenicity. Unit 13 said a sensitized patient can react to it anaphylactically.
Here is the fourth consequence. Give enough horse protein and the patient makes antibody against it β while the horse protein is still circulating. Antigen and antibody meet in the blood, at the mid-range ratio, forming exactly the medium-sized complexes of Β§1. One to two weeks later: fever, weakness, vasculitis.
The timing is the giveaway and worth remembering: type I is minutes, type III is 1β3 weeks, because type III must wait for a primary antibody response to occur.
- What causes serum sickness, and how long after? → Large amounts of antiserum; symptoms 1β2 weeks later
- What is rheumatoid factor? → An IgM auto-antibody against degenerated IgG
- Where do complexes deposit in RA? → The synovium of small joints
- What are the auto-antigen and auto-antibody in SLE? → DNA and histones; antinuclear antibody (ANA)
- How long after streptococcal infection does glomerulonephritis appear? → 2β3 weeks
Type IV β the properties β β β
Type IV is the odd one out, and every one of its three defining properties is a negative compared with types I to III.
- Delay in time β 24β72 hours after the second contact with antigen (the deck also gives 36β48 h for the classic reaction)
- Recruitment of macrophages
- NO antibody and NO complement involved
The delay is not incidental β it is diagnostic. Types I, II and III are all antibody-mediated, and antibody is already present in a sensitized person, so those reactions begin within minutes to hours.
Type IV has no pre-formed effector waiting. It needs sensitized T cells to find the antigen, be activated, secrete cytokines, and then recruit and activate macrophages β and cells must physically migrate to the site. That takes a day or more.
So the 24β72 hour delay is direct evidence that no antibody is involved. If you know only one thing about type IV, know that timing tells you the mechanism.
- How long is the type IV delay? → 24β72 hours after the second antigen contact
- Which cell is recruited? → The macrophage
- Is antibody or complement involved? → Neither
- Why is it delayed? → T cells must be activated and cells must migrate; there is no pre-formed effector
Type IV mechanism β β β
- Antigen β intracellular bacteria, viruses, parasites or chemicals β is taken up by APCs.
- T cells are activated, proliferate and differentiate into effector CD4βΊ Th1 and effector CD8βΊ CTL, plus memory T cells.
- On second contact, effector CD4βΊ Th1 cells secrete cytokines that activate macrophages β clearing the microbe with accompanying tissue damage.
- Effector CD8βΊ CTLs specifically kill target cells.
The tissue damage is a by-product of a genuinely useful antimicrobial response.
| Mediator | Role |
|---|---|
| Chemokines | Recruitment of macrophages |
| IFN-Ξ³ | Activates macrophages |
| TNF-Ξ± and TNF-Ξ² | Local tissue injury; increase adhesion-molecule expression on vascular endothelium |
| CTL killing | Lyses target cells directly |
This is the Unit 5 Th1/Th2 table doing real clinical work, and it is worth noticing that the same knowledge answers the True/False trap in Unit 5 and this statement here.
- Which T cells mediate type IV? → CD4βΊ Th1 and CD8βΊ CTL
- Which cytokine activates macrophages? → IFN-Ξ³
- Which cytokines cause local tissue injury? → TNF-Ξ± and TNF-Ξ²
- Which Th subset drives type IV, and which drives type I? → Th1 β type IV; Th2 β type I
Type IV diseases β β β
1 Β· Infectious DTH
In tuberculosis, the first infection can give miliary tuberculosis; a second produces a localised reaction thanks to memory immunity, and repeated occurrence produces chronic granuloma. The skin test is the OT (Old Tuberculin) test. BCG is a strain of tubercle bacillus that has lost the power to cause tuberculosis but retains its antigenicity.
| OT test result | Interpretation |
|---|---|
| Positive β red indurated lesion ~5 mm at 24β48 h | β The patient has contacted the bacterium β‘ The patient's cellular immunity is normal |
| Strongly positive (+++) | Infection |
| Negative at 72 h | β The vaccine has lost efficacy β‘ The patient has never contacted the bacterium β’ Immunodeficiency |
Look at the negative row carefully, because it contains a clinically important trap. A negative tuberculin test usually means the patient has never met the organism β reassuring. But it can also mean their cellular immunity is too weak to mount the reaction.
So in a patient who is severely ill, malnourished or HIV-positive, a negative test may be anergy rather than absence of infection. The test does not detect the bacterium; it detects the patient's T-cell response to it. If the T cells cannot respond, the test is silent no matter how much organism is present.
That is also why a positive test is stated as two conclusions in the table: the patient met the bacterium and their cellular immunity works.
2 Β· Contact dermatitis
The agent is a hapten β nickel, cosmetics, oil, paint, dye, medicine, or the leather of a watch strap or waistband. It binds the keratin of the cuticle, and the conjugate becomes the antigen. Effector T cells then produce local red swelling and blistering.
Note the loop back to Unit 2. Nickel is far too small to be immunogenic alone β it is the textbook hapten. Coupling to skin protein supplies the carrier, exactly as penicillin coupling to serum albumin did. Same principle, different outcome: penicillin's conjugate drives IgE and type I; nickel's drives T cells and type IV.
The deck makes a point worth carrying: the term hypersensitivity is somewhat misleading, for it suggests a DTH response is always detrimental. In reality DTH is an important effector form of cell-mediated immunity β in essence it is inflammation. It is how you contain tuberculosis and other intracellular organisms.
The granuloma is the clearest illustration: it is tissue damage, and it is also the body successfully walling off an organism it cannot kill outright. Whether you call that pathology or defence depends on where you stand.
- How is the OT test read, and when? → Red indurated lesion about 5 mm at 24β48 h
- What does a positive test tell you? → The patient has met the bacterium AND their cellular immunity is normal
- Give three reasons for a negative test. → Vaccine lost efficacy; never contacted the bacterium; immunodeficiency
- What is BCG? → A tubercle bacillus strain that has lost virulence but kept antigenicity
- What causes contact dermatitis? → A hapten (nickel, dye, leather) binding keratin of the cuticle to form the antigen
All four types compared β β β
| Type I | Type II | Type III | Type IV | |
|---|---|---|---|---|
| Name | Anaphylactic / immediate | Cytotoxic / cytolytic | Immune complex | Delayed-type (DTH) |
| Mediated by | IgE | IgG, IgM on cell surface | Immune complexes | T cells |
| Antigen | Allergen (soluble) | Cell-surface antigen | Soluble antigen | Intracellular microbes, chemicals |
| Effector cells | Mast cells, basophils, eosinophils | Complement, macrophages, NK cells | Complement, neutrophils, platelets | Th1, CTL, macrophages |
| Th subset | Th2 | β | β | Th1 |
| Timing | Minutes | Hours | 1β3 weeks | 24β72 hours |
| Complement? | No (IgE does not fix) | Yes | Yes | No |
| Diseases | Asthma, rhinitis, urticaria, anaphylaxis | Transfusion reaction, HDN, haemolytic anaemia, hyperthyroidism | SLE, RA, serum sickness, glomerulonephritis, Arthus | Contact dermatitis, tuberculin reaction, granuloma |
Step 1 β is it antibody or T cell? If the disease involves T cells, macrophages, granulomas or a delay of days, it is type IV. Everything else is antibody.
Step 2 β where is the antigen? On a mast cell via IgE β type I. Fixed on a target cell surface β type II. Soluble, forming complexes that deposit β type III.
Two questions place any disease, and they are enough for MCQs Q17βQ20.
- Which type is cell-mediated? → Type IV only
- Which two types activate complement? → II and III
- Which type is fastest, and which slowest? → Type I (minutes); type III (1β3 weeks)
- Which Th subset drives type I and which type IV? → Th2 and Th1
- Where is the antigen in types II and III? → Cell surface (II) vs soluble (III)
Revision layer
The exam map for this unit
| Section | Item | From |
|---|---|---|
| III. MCQ Q18 | SLE is caused by type III | Β§4 |
| IV. True/False Q11 | Th1 in type IV, Th2 in type I β T | Β§6 |
| β | Supplies the distractors for MCQ Q17, Q19 and Q20 in Units 13 and 14 | Β§8 |
The whole unit on one screen
| Question | Answer |
|---|---|
| Which IC size causes disease? | Medium (β19S) β too big to filter, too small to phagocytose |
| Where do complexes deposit? | Joint synovium Β· glomerular basement membrane Β· choroid plexus |
| Which cell does the damage in type III? | The neutrophil, releasing lytic enzymes |
| Local IC diseases? | Arthus reaction Β· insulin Arthus-like Β· pigeon breeder's and farmer's lung |
| Systemic IC diseases? | Serum sickness Β· post-streptococcal glomerulonephritis Β· RA Β· SLE |
| Rheumatoid factor? | IgM auto-antibody against degenerated IgG |
| SLE auto-antibody? | Antinuclear antibody (ANA), against DNA and histones |
| Three properties of type IV? | 24β72 h delay Β· macrophage recruitment Β· no antibody or complement |
| Type IV effector cells? | CD4βΊ Th1 and CD8βΊ CTL |
| Which cytokine activates macrophages? | IFN-Ξ³ |
| OT test positive? | Red induration ~5 mm at 24β48 h |
| Negative OT test can mean? | No contact β or immunodeficiency |
| Contact dermatitis mechanism? | Hapten binds keratin β antigen β effector T cells |
- Why is only the medium-sized immune complex pathogenic? → Too small for phagocytes, too large to filter, and it activates complement strongly
- Which cell causes the tissue damage in type III? → The neutrophil, recruited by C3a/C5a/C5b67
- Name four systemic immune-complex diseases. → Serum sickness, post-streptococcal glomerulonephritis, rheumatoid arthritis, SLE
- Give the three properties of type IV. → Delayed 24β72 h, macrophage recruitment, no antibody or complement
- Why is type IV delayed? → T cells must be activated and migrate; there is no pre-formed effector
- What does a negative tuberculin test possibly indicate? → Immunodeficiency, not just absence of infection
- Place SLE, asthma, HDN and contact dermatitis. → III, I, II, IV