Comprehensive Study Notes on Type III and Type IV Hypersensitivity

Physiology of Normal Immune Complex Clearance and the Role of HRG

Under normal physiological conditions, immune complexes, which consist of an antigen bound to an antibody, are safely and efficiently removed from the blood circulation to prevent tissue damage. Phagocytes play a crucial role in this process by utilizing their $IgG$ $Fc$ receptors to recognize and engulf these complexes. Additionally, Red Blood Cells ($RBCs$) equipped with $C3b$ receptors (also known as $CR1$) perform a transport function by carrying immune complexes through the circulatory system to the liver. Once in the liver, specialized macrophages known as Kupffer cells identify and destroy these complexes.

A specific liver protein identified as Histidine-Rich Glycoprotein ($HRG$) is instrumental in the maintenance of immune homeostasis. $HRG$ assists in the removal of immune complexes, binds to naked $DNA$, and facilitates the clearance of apoptotic cells. By performing these functions, $HRG$ can effectively hide certain epitopes from autoantibodies, such as rheumatoid factor and anti-$dsDNA$ antibodies, thereby reducing the likelihood of autoimmune reactions within the body.

General Mechanisms and Deposition of Type III Hypersensitivity

Type III hypersensitivity, also referred to as immune complex-mediated hypersensitivity, occurs when the normal clearance mechanisms of the body are overwhelmed by the excessive formation of antigen-antibody complexes. While large immune complexes are typically removed rapidly and are considered harmless, small or intermediate-sized complexes are more pathogenic. These smaller complexes circulate in the bloodstream for longer durations because they bind poorly to $Fc$ receptors on phagocytes.

When these small or intermediate complexes deposit into tissues, they trigger an inflammatory response that can lead to either systemic immune complex disease or localized tissue damage. Common sites for the deposition of these complexes include the kidneys (specifically the glomeruli), the skin, the joints, the choroid plexus, and the ciliary artery of the eye. The antigens involved in these reactions can be exogenous, such as bacteria, viruses, or injected foreign proteins, or they can be endogenous, such as the self-antigens (like $DNA$) seen in systemic lupus erythematosus ($SLE$). In $SLE$, the deposition of immune complexes in the glomeruli leads to a condition known as lupus nephritis.

Cellular and Molecular Pathways of Tissue Injury in Type III Reactions

The primary mechanism of tissue injury in Type III hypersensitivity involves the activation of the complement system. The process begins when immune complexes fix complement, leading to the activation of the complement cascade. This activation results in the production of the anaphylatoxins $C3a$ and $C5a$. These molecules increase vascular permeability and serve as chemoattractants that recruit neutrophils to the site of deposition. Neutrophils then release lysosomal enzymes, which are the direct cause of the resulting tissue damage.

The antibodies most commonly involved in these reactions are $IgG$, though $IgM$ is sometimes implicated. The presence of $IgG$ $Fc$ receptors, specifically $CD16$, on leukocytes is vital for the inflammatory process. Beyond neutrophil recruitment, $C3a$ and $C5a$ stimulate mast cells and basophils to release arachidonic acid metabolites and various chemokines. These mediators further recruit a variety of inflammatory cells, including eosinophils, macrophages, and basophils. Macrophages contribute by releasing pro-inflammatory cytokines such as $TNF-\alpha$ and $IL-1$. Additionally, platelets may form microthrombi and release Platelet-Derived Growth Factor ($PDGF$), which stimulates cellular proliferation in the affected area.

Phases and Characteristics of Systemic Immune Complex Disease

Systemic immune complex disease typically progresses through three distinct phases. The first phase is the formation of immune complexes, where antigens and antibodies combine within the bloodstream. The second phase involves the deposition of these complexes into various tissues throughout the body. The third and final phase is the initiation of an inflammatory response that leads to tissue damage.

Several factors influence the pathogenicity of these complexes. The size of the complex is paramount; large complexes are easily cleared by the mononuclear phagocyte system, whereas small and intermediate complexes bypass these filters. Consequently, any defect in the function of the mononuclear phagocyte system significantly increases the risk and severity of Type III diseases. The kidneys are particularly vulnerable to deposition because the glomeruli serve as a filtration system for high volumes of blood, effectively trapping the circulating small complexes.

Clinical Prototypes: Serum Sickness and Monoclonal Antibody Therapy

Serum sickness serves as the prototype for systemic Type III hypersensitivity. Historically, this condition was observed in patients treated for diphtheria or tetanus using antiserum derived from horses. The human body recognizes foreign horse proteins as antigens and produces antibodies against them. As antigen-antibody complexes form and deposit, patients develop clinical features such as fever, arthralgia (joint pain), lymphadenopathy (swollen lymph nodes), and skin rashes.

While horse antiserum is less common today, similar reactions were noted with older varieties of rodent monoclonal antibodies before the widespread development of humanized antibodies. Furthermore, certain non-protein drugs can also trigger serum sickness-like reactions. Histologically, the deposition in serum sickness is often described as having a "lumpy-bumpy" appearance when visualized, distinguishing it from other patterns of immune deposition.

Infection-Associated and Chronic Type III Hypersensitivity Disorders

Many chronic infections lead to Type III hypersensitivity due to the persistent presence of antigens. Rheumatic fever is a classic example that occurs following an infection with group A streptococci. In this condition, streptococcal antigens induce the production of antibodies that cross-react with host tissues, including heart muscle, cartilage, and the glomerular basement membrane, leading to widespread inflammation.

Rheumatoid arthritis involves the production of Rheumatoid Factor, an $IgM$ autoantibody directed against the $Fc$ portion of the host's own $IgG$. The resulting immune complexes deposit in the joints, causing chronic inflammation and joint destruction. Goodpasture syndrome is a unique case often following viral respiratory infections; antibodies bind directly to the basement membranes of the lungs and kidneys, activating complement and recruiting neutrophils. Although often considered Type II hypersensitivity because the antibodies bind to fixed tissue, it shares mechanical commonalities with Type III, resulting in pulmonary hemorrhage and glomerulonephritis. Unlike the "lumpy-bumpy" deposits of serum sickness, Goodpasture syndrome is characterized by linear, "ribbon-like" deposits. Other infections associated with large-scale immune complex formation include malaria, leprosy, and dengue.

Localized Type III Reactions: The Arthus Reaction and Occupational Lung Diseases

The Arthus reaction is the prototype for localized Type III hypersensitivity. This reaction occurs in a person who has already been sensitized and has preformed $IgG$ antibodies. Upon local re-exposure to the antigen, insoluble immune complexes form near vessel walls, activating complement and leading to neutrophil accumulation. This results in vessel damage, hemorrhage, and localized tissue necrosis, characterized clinically by erythema and edema.

Farmer’s Lung is an occupational lung disease caused by the inhalation of spores from moldy hay, specifically thermophilic actinomycetes. Affected individuals produce $IgG$ against these spores, and subsequent inhalation leads to the formation of immune complexes in the lungs, triggering an inflammatory reaction similar to the Arthus reaction. Symptoms typically include respiratory distress and pneumonitis, occurring $6-8\,hours$ after exposure. Other similar pulmonary conditions include pigeon breeder's disease, cheese washer's disease, bagassosis, maple bark stripper's disease, paprika worker's disease, and thatched roof worker's lung. Additionally, deficiencies in complement proteins $C1$, $C2$, or $C4$ can impair the normal clearance and breakdown of immune complexes, leading to increased deposition and inflammation.

Fundamentals and Temporal Dynamics of Type IV Hypersensitivity

Type IV hypersensitivity is distinct from the first three types because it is mediated by $T$ cells rather than antibodies. It is commonly referred to as Delayed-Type Hypersensitivity ($DTH$) because the response typically develops over a period of $48-72\,hours$. This delay is necessary to allow for the activation, proliferation, and cytokine release of specific $T$ cells.

The central mechanism of $DTH$ involves activated $T$ cells releasing cytokines and chemokines that recruit macrophages, monocytes, Natural Killer ($NK$) cells, and other inflammatory cells to the site of the antigen. While $DTH$ is beneficial for protection against viruses, bacteria (such as Mycobacterium tuberculosis), fungi, and tumors, it can also be harmful. It is the primary driver behind allergic contact dermatitis, various autoimmune diseases, and the rejection of transplanted tissues. In the skin, Antigen-Presenting Cells ($APCs$) known as Langerhans cells activate $CD4$ memory $T$ cells, leading to inflammation, plasma leakage, and swelling.

Phases of Delayed-Type Hypersensitivity: Sensitization versus Elicitation

The $DTH$ response occurs in two distinct stages: the sensitization stage and the elicitation stage. The sensitization stage occurs during the first exposure to an antigen. Over the course of $1-2\,weeks$, the antigen activates $TH1$ and $TH17$ cells, leading to their clonal expansion. At this point, the individual is "sensitized" but does not yet show a clinical reaction.

The elicitation stage occurs upon re-exposure to the same antigen in a previously sensitized person. Memory $TH1$ and $TH17$ cells quickly recognize the antigen and release inflammatory cytokines, which recruit macrophages and other leukocytes. This stage takes between $18-48\,hours$ to become apparent, and in some instances, the reaction can transition into a chronic inflammatory state. The timing of $48-72\,hours$ is the standard window for the peak clinical manifestation of these reactions.

Cytokine Profiles and Specific Cellular Involvement in DTH

Several specific cytokines are essential for the propagation of a $DTH$ response. $IFN-\gamma$ is a primary cytokine that activates macrophages, enhancing their ability to phagocytose and destroy pathogens. Chemokines such as $MCP-1$, $RANTES$, $MIP-1\alpha$, and $MIP-1\beta$ are responsible for the recruitment of inflammatory cells. $TNF-\alpha$ and $TNF-\beta$ contribute to tissue damage and increase the expression of adhesion molecules on vascular endothelium, facilitating leukocyte migration. $IL-12$ is also involved, acting to suppress $TH2$ responses while promoting $TH1$ responses.

While $CD4$ cells are classical mediators, $CD8$ $T$ cells also participate in $DTH$, particularly when certain chemicals enter host cells and modify internal proteins. These modified peptides are presented on $MHC\,I$ molecules, signaling $CD8$ $T$ cells to kill the affected host cells. An example of this is the reaction to the chemical pentadecacatechol found in poison ivy. Activated macrophages play the role of the main effector cells; they ingest pathogens, release lysosomal enzymes, and produce reactive oxygen species like peroxide and superoxide radicals to destroy microbes, tumors, or foreign tissues.

Contact Sensitivity: Pathogenesis of Contact Dermatitis

Contact sensitivity, or contact dermatitis, is a localized Type IV reaction in the skin following contact with an allergen, peaking between $48-72\,hours$. The classic example is poison ivy dermatitis. The oil in poison ivy contains catechols with long hydrocarbon chains that penetrate the skin and bind to host proteins, forming hapten-carrier complexes. Other common sensitizers include $DNCB$, nickel, and chromium.

The mechanism begins with Langerhans cells presenting the haptenated antigens to $T$ cells, leading to $TH1$ expansion. Upon re-exposure, the $DTH$ response is triggered. In some cases, enough antigen may remain in the skin to trigger elicitation without a new external exposure. Histologically, contact dermatitis is characterized by the formation of intraepithelial blisters, mononuclear cell infiltrates, spongiosis (intercellular edema), and epidermal separation. Diagnosis is typically made using a Patch Test, where the suspected antigen is placed under an occlusive dressing for approximately $3\,days$; a positive result is indicated by erythema and induration.

Granulomatous Hypersensitivity and Chronic Antigen Persistence

When an antigen persists within the body and cannot be easily cleared, the immune system may develop a granulomatous hypersensitivity response. This is seen in infections such as Schistosoma mansoni eggs, Mycobacterium leprae, and Mycobacterium tuberculosis. The persistent activation of macrophages causes them to transform into epithelioid cells and fuse into multinucleated giant cells, eventually forming a granuloma.

Maximal granuloma formation typically occurs between $21-28\,days$. These structures can lead to significant clinical complications, including fibrosis and caseous necrosis. Chronic activation of autoreactive $TH1$ cells in this manner also contributes to autoimmune diseases like rheumatoid arthritis, type 1 diabetes, and multiple sclerosis. In tuberculosis, granulomas often feature a surrounding "cuff" of lymphocytes. Notably, much of the tissue damage in these diseases results from the host's own $DTH$ response rather than direct action by the infecting organism.

Tuberculin Skin Testing and Advanced Diagnostic Modalities

The Tuberculin or $PPD$ test is the classic clinical application of $DTH$ testing. Purified Protein Derivative ($PPD$) is injected intradermally; in previously sensitized individuals, erythema and induration (hardening) develop at the injection site within $48-72\,hours$. This induration is primarily caused by the deposition of fibrin. Histological examination of the site reveals infiltrates of monocytes and macrophages, a small number of lymphocytes, and perivascular cuffing.

False negative results, known as anergy, can occur in immunosuppressed patients, such as those with $HIV$ or those undergoing chemotherapy. False positive results often occur in individuals who have received the $BCG$ vaccine ($bacille\,Calmette-Guérin$), an attenuated strain of Mycobacterium bovis. Due to these limitations, the $ELISPOT$ test is often preferred. This test measures the $IFN-\gamma$ released by $T$ cells sensitized specifically to Mycobacterium tuberculosis ($MTB$). It can detect $M.\,tuberculosis$, $M.\,bovis$, and $M.\,africanum$, and it usually yields a negative result in individuals whose only exposure was the $BCG$ vaccine or environmental mycobacteria.

Transplantation Rejection and Autoimmune DTH Reactions

Allograft rejection is a complex Type IV hypersensitivity reaction that occurs when tissues are transplanted between genetically different individuals, particularly due to differences in major histocompatibility complex ($MHC$) molecules. The mechanism involves $T$ cells and monocytes infiltrating the graft, which leads to the destruction of blood vessels, deprivation of nutrients to the tissue, and eventual necrosis.

Another specialized form is Cutaneous Basophil Hypersensitivity, an erythematous reaction characterized by basophil infiltrates rather than the fibrin-heavy induration of a typical $PPD$ test. This is seen after repeated intradermal antigen injections and is associated with tick bites, poison ivy, renal graft rejection, and conjunctivitis, suggesting basophils may assist in immunity against parasites. Treatment for severe $DTH$ involves immunosuppressive drugs such as corticosteroids (topical or systemic), or calcineurin inhibitors like cyclosporine and tacrolimus. Mild cases often resolve spontaneously once the triggering antigen is removed.