Angioedema is an area of swelling of the lower layer of skin and tissue just under the skin or mucous membranes. The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs. Often it is associated with hives, which are swelling within the upper skin. Onset is typically over minutes to hours.

The underlying mechanism typically involves histamine or bradykinin. The version related to histamine is to due an allergic reaction to agents such as insect bites, foods, or medications. The version related to bradykinin may occur due to an inherited problem known as C1 esterase inhibitor deficiency, medications known as angiotensin converting enzyme inhibitors, or a lymphoproliferative disorder.

Efforts to protect the airway may include intubation or cricothyroidotomy. Histamine related angioedema can be treated with antihistamines, corticosteroids, and epinephrine. In those with bradykinin related disease a C1 esterase inhibitor, ecallantide, or icatibant may be used. Fresh frozen plasma may be used instead. In the United States the disease affects about 100,000 people a year.

The skin of the face, normally around the mouth, and the mucosa of the mouth and/or throat, as well as the tongue, swell over the period of minutes to hours. The swelling can also occur elsewhere, typically in the hands. The swelling can be itchy or painful. There may also be slightly decreased sensation in the affected areas due to compression of the nerves. Urticaria (hives) may develop simultaneously.

In severe cases, stridor of the airway occurs, with gasping or wheezy inspiratory breath sounds and decreasing oxygen levels. Tracheal intubation is required in these situations to prevent respiratory arrest and risk of death.

Sometimes, the cause is recent exposure to an allergen (e.g. peanuts), but more often it is either idiopathic (unknown) or only weakly correlated to allergen exposure.

In hereditary angioedema, often no direct cause is identifiable, although mild trauma, including dental work and other stimuli, can cause attacks. There is usually no associated itch or urticaria, as it is not an allergic response. Patients with HAE can also have recurrent episodes (often called "attacks") of abdominal pain, usually accompanied by intense vomiting, weakness, and in some cases, watery diarrhea, and an unraised, nonitchy splotchy/swirly rash. These stomach attacks can last one to five days on average, and can require hospitalization for aggressive pain management and hydration. Abdominal attacks have also been known to cause a significant increase in the patient's white blood cell count, usually in the vicinity of 13,000 to 30,000. As the symptoms begin to diminish, the white count slowly begins to decrease, returning to normal when the attack subsides. As the symptoms and diagnostic tests are almost indistinguishable from an acute abdomen (e.g. perforated appendicitis) it is possible for undiagnosed HAE patients to undergo laparotomy (operations on the abdomen) or laparoscopy (keyhole surgery) that turns out to have been unnecessary.

HAE may also cause swelling in a variety of other locations, most commonly the limbs, genitals, neck, throat and face. The pain associated with these swellings varies from mildly uncomfortable to agonizing pain, depending on its location and severity. Predicting where and when the next episode of edema will occur is impossible. Most patients have an average of one episode per month, but there are also patients who have weekly episodes or only one or two episodes per year. The triggers can vary and include infections, minor injuries, mechanical irritation, operations or stress. In most cases, edema develops over a period of 12–36 hours and then subsides within 2–5 days.

A rare autoimmune disease characterized by recurrent urticaria (nettle rash), first described in the 1970s. There is no defined paradigm for the syndrome aetiology and severity in progression. Diagnosis is confirmed with the identification of at least two conditions from: venulitis on skin biopsy, arthritis, ocular inflammation, abdominal pain or positive C1q antibodies to immune complexes. It is this last category, anti-C1q antibodies, that all HUV patients test positive for. "In vitro" experiments and mouse models of the disease have not thoroughly determined the link between these antibodies and the disease, even though the link is so pronounced.

The main sign of the disease is life-threatening, recurrent bacterial or fungal soft tissue infections. These infections are often apparent at birth and may spread throughout the body. Omphalitis (infection of the umbilical cord stump) is common shortly after birth. Other signs include delayed separation of the umbilical cord, periodontal disease, elevated neutrophils, and impaired wound healing, but not increased vulnerability to viral infections or cancer. Such patients have fever as the manifestation of infection, inflammatory responses are indolent.

Urticarial vasculitis (also known as "chronic urticaria as a manifestation of venulitis", "hypocomplementemic urticarial vasculitis syndrome", "hypocomplementemic vasculitis" and "unusual lupus-like syndrome") is a skin condition characterized by fixed urticarial lesions that appear histologically as a vasculitis.

Complement 2 deficiency is a type of complement deficiency caused by any one of several different alterations in the structure of complement component 2.

It has been associated with an increase in infections.

It can present similarly to systemic lupus erythematosus (SLE).

Serum sickness in humans is a reaction to proteins in antiserum derived from a non-human animal source, occurring 4–10 days after exposure. It is a type of hypersensitivity, specifically immune complex hypersensitivity (type III). The term serum sickness-like reaction (SSLR) is occasionally used to refer to similar illnesses that arise from the introduction of certain non-protein substances, such as penicillin. It was first characterized by Clemens von Pirquet and Béla Schick in 1906.

Type III hypersensitivity occurs when there is accumulation of immune complexes (antigen-antibody complexes) that have not been adequately cleared by innate immune cells, giving rise to an inflammatory response and attraction of leukocytes. Such reactions progressing to the point of disease produce immune complex diseases.

Granulomatosis with polyangiitis (GPA; formerly known as Wegener's granulomatosis). Systemic vasculitis of medium and small arteries, including venules and arterioles. Produces granulomatous inflammation of the respiratory tracts and necrotizing, pauci-immune glomerulonephritis. Most common cause of saddle nose deformity in USA (nose flattened due to destruction of nasal septum by granulomatous inflammation). Almost all patients with WG have c-ANCA, but not vice versa. Current treatment of choice is cyclophosphamide. At least 2 out of 4 criteria yields sensitivity and specificity of 88 and 92%.

- nasal or oral inflammation (oral ulcers or purulent/bloody nasal discharge, may be painful)

- abnormal CXR showing nodules, infiltrates, cavities

- microscopic hematuria or RBC casts

- vessel biopsy shows granulomatous inflammation

- Peak incidence: ages 40–60, males > females

Eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome). Affects medium and small vessels with vascular and extravascular granulomatosis. Classically involves arteries of lungs and skin, but may be generalized. At least 4 criteria yields sensitivity and specificity of 85 and 99.7%.

- asthma (history of wheezeing or presently wheezing)

- eosinophilia > 10% on CBC

- mononeuropathy or polyneuropathy

- migratory or transient pulmonary opacities on chest x-ray (CXR)

- paranasal sinus abnormalities

- vessel biopsy showing eosinophils in extravascular areas

Microscopic polyarteritis/polyangiitis. Affects capillaries, venules, or arterioles. Thought to be part of a group that includes granulomatosis with polyangiitis since both are associated with ANCA and similar extrapulmonary manifestations. Patients do not usually have symptomatic or histologic respiratory involvement.

Hypersensitivity vasculitis (allergic vasculitis). Usually due to a hypersensitivity reaction to a known drug. Drugs most commonly implicated are penicillin, sulphonamides and thiazide diuretics. There is presence of skin vaculitis with palpable petechiae or purpura. Biopsy of these lesions reveal inflammation of the small vessels, termed leukocytoclastic vasculitis, which is most prominent in postcapillary venules. At least 3 out of 5 criteria yields sensitivity and specificity of 71 and 84%:

- age > 16

- use of possible triggering drug in relation to symptoms

- palpable purpura

- maculopapular rash

- skin biopsy showing neutrophils around vessel

IgA vasculitis (IgAV; formerly known as Henoch-Schonlein purpura). Systemic vasculitis due to tissue deposition of IgA-containing immune complexes. Biopsy of lesions shows inflammation of small vessels. It is considered a form of hypersensitivity vasculitis but is distinguished by prominent deposits of IgA. This is the most common vasculitis in children. Presence of 3 or more criteria yielded sensitivity of 87% while less than 2 criteria yielded hypersensitivity vasculitis in 74%:

- palpable purpura (usually of buttocks & legs)

- bowel angina

- GI bleed

- hematuria

- onset < 20 years

- no new medications

Essential cryoglobulinemic vasculitis. Most often due to hepatitis C infection, immune complexes of cryoglobulins --- proteins that consists of immunoglobulins and complement and precipitate in the cold while dissolving upon rewarming --- are deposited in walls of capillaries, venules, or arterioles. Therefore, complement will be low with histology showing vessel inflammation with immune deposits.

These are a few specialized autoimmune disorders resulting from environmental rather than genetic causes, which mimic the genotypic disorders.

The complement system is part of the innate as well as the adaptive immune system; it is a group of circulating proteins that can bind pathogens and form a membrane attack complex. Complement deficiencies are the result of a lack of any of these proteins. They may predispose to infections but also to autoimmune conditions.

1. C1q deficiency (lupus-like syndrome, rheumatoid disease, infections)

2. C1r deficiency (idem)

3. C1s deficiency

4. C4 deficiency (lupus-like syndrome)

5. C2 deficiency (lupus-like syndrome, vasculitis, polymyositis, pyogenic infections)

6. C3 deficiency (recurrent pyogenic infections)

7. C5 deficiency (Neisserial infections, SLE)

8. C6 deficiency (idem)

9. C7 deficiency (idem, vasculitis)

10. C8a deficiency

11. C8b deficiency

12. C9 deficiency (Neisserial infections)

13. C1-inhibitor deficiency (hereditary angioedema)

14. Factor I deficiency (pyogenic infections)

15. Factor H deficiency (haemolytic-uraemic syndrome, membranoproliferative glomerulonephritis)

16. Factor D deficiency (Neisserial infections)

17. Properdin deficiency (Neisserial infections)

18. MBP deficiency (pyogenic infections)

19. MASP2 deficiency

20. Complement receptor 3 (CR3) deficiency

21. Membrane cofactor protein (CD46) deficiency

22. Membrane attack complex inhibitor (CD59) deficiency

23. Paroxysmal nocturnal hemoglobinuria

24. Immunodeficiency associated with ficolin 3 deficiency

Symptoms can take as long as 14 days after exposure to appear, and may include signs and symptoms commonly associated with hypersensitivity or infections.

- rashes

- itching

- joint pain (arthralgia), especially finger and toe joints

- fever, as high as 40 °C and usually appears before rash

- lymphadenopathy (swelling of lymph nodes), particularly near the site of injection, head and neck

- malaise

- hypotension (decreased blood pressure)

- splenomegaly (enlarged spleen)

- glomerulonephritis

- proteinuria

- hematuria

- shock

Some clinical examples:

Other examples are:

- Subacute bacterial endocarditis

- Symptoms of malaria

In immunology, the Arthus reaction (, ) is a type of local type III hypersensitivity reaction. Type III hypersensitivity reactions are immune complex-mediated, and involve the deposition of antigen/antibody complexes mainly in the vascular walls, serosa (pleura, pericardium, synovium), and glomeruli. This reaction is usually encountered in experimental settings following the injection of antigens.

Leukocyte adhesion deficiency-1 (LAD1) is a rare and often fatal genetic disorder in humans.

The key symptoms of PFAPA are those in its name: periodic high fever at intervals of about 3–5 weeks, as well as aphthous ulcers, pharyngitis and/or adenitis. In between episodes, and even during the episodes, the children appear healthy. At least 6 months of episodes. Diagnosis requires recurrent negative throat cultures and that other causes (such as EBV, CMV, FMF) be excluded.

Periodic fever, aphthous stomatitis, pharyngitis and adenitis or periodic fever aphthous pharyngitis and cervical adenopathy (PFAPA) syndrome is a medical condition, typically starting in young children, in which high fever occurs periodically at intervals of about 3–5 weeks, frequently accompanied by aphthous-like ulcers, pharyngitis and/or cervical adenitis (cervical lymphadenopathy). The syndrome was described in 1987 and named two years later.

The Arthus reaction was discovered by Nicolas Maurice Arthus in 1903. Arthus repeatedly injected horse serum subcutaneously into rabbits. After four injections, he found that there was edema and that the serum was absorbed slowly. Further injections eventually led to gangrene.

Diffuse proliferative nephritis (DPN) or glomerulonephritis (DPGN) is a type of glomerulonephritis that is the most serious form of renal lesions in SLE and is also the most common, occurring in 35% to 60% of patients. Most of the glomeruli show endothelial and mesangial proliferation affecting the entire glomerulus, leading to diffuse hypercellularity of the glomeruli, producing in some cases epithelial crescents that fill Bowman's space. When extensive, immune complexes create an overall thickening of the capillary wall, resembling rigid "wire loops" on routine light microscopy. Electron microscopy reveals electron-dense subendothelial immune complexes (between endothelium and basement membrane). Immune complexes can be visualized by staining with fluorescent antibodies directed against immunoglobulins or complement, resulting in a granular fluorescent staining pattern. In due course, glomerular injury gives rise to scarring (glomerulosclerosis). Most of these patients have hematuria with moderate to severe proteinuria, hypertension, and renal insufficiency.

The initial signs and symptoms of NBD are usually very general. This makes NBD hard to diagnose until the patients experience a severe neurological damage. In addition, the combination of symptoms varies among patients.

Complement 3 deficiency is a genetic condition affecting complement component 3.

It can cause systemic lupus erythematosus-like symptoms.

It can lead to an increase in pyogenic infections from encapsulated bacteria.

The main symptom is meningoencephalitis which happens in ~75% of NBD patients. Other general symptoms of Behçet's disease are also present among parenchymal NBD patients such as fever, headache, genital ulcers, genital scars, and skin lesions. When the brainstem is affected, ophthalmoparesis, cranial neuropathy, and cerebellar or pyramidal dysfunction may be observed. Cerebral hemispheric involvement may result in encephalopathy, hemiparesis, hemisensory loss, seizures, dysphasia, and mental changes including cognitive dysfunction and

psychosis. As for the spinal cord involvement, pyramidal signs in the limbs, sensory level dysfunction, and, commonly, sphincter dysfunction may be observed.

Some of the symptoms are less common such as stroke (1.5%), epilepsy (2.2–5%), brain tumor, movement disorder, acute meningeal syndrome, and optic neuropathy.

Eosinophilia can be idiopathic (primary) or, more commonly, secondary to another disease. In the Western World, allergic or atopic diseases are the most common causes, especially those of the respiratory or integumentary systems. In the developing world, parasites are the most common cause. A parasitic infection of nearly any bodily tissue can cause eosinophilia.

Diseases that feature eosinophilia as a sign include:

- Allergic disorders

- Asthma

- Hay fever

- Drug allergies

- Allergic skin diseases

- Pemphigus

- Dermatitis herpetiformis

- IgG4-related disease

- Parasitic infections

- Addison's disease and stress-induced suppression of adrenal gland function

- Some forms of malignancy

- Acute lymphoblastic leukemia

- Chronic myelogenous leukemia

- Eosinophilic leukemia

- Clonal eosinophilia

- Hodgkin lymphoma

- Some forms of non-Hodgkin lymphoma

- Lymphocyte-variant hypereosinophilia

- Systemic mastocytosis

- Systemic autoimmune diseases

- Systemic lupus erythematosus

- Kimura disease

- Eosinophilic granulomatosis with polyangiitis

- Eosinophilic fasciitis

- Eosinophilic myositis

- Eosinophilic esophagitis

- Eosinophilic gastroenteritis

- Cholesterol embolism (transiently)

- Coccidioidomycosis (Valley fever), a fungal disease prominent in the US Southwest.

- Human immunodeficiency virus infection

- Interstitial nephropathy

- Hyperimmunoglobulin E syndrome, an immune disorder characterized by high levels of serum IgE

- Idiopathic hypereosinophilic syndrome.

- Congenital disorders

- Hyperimmunoglobulin E syndrome

- Omenn syndrome

- Familial eosinophilia

Complement 4 deficiency is a genetic condition affecting complement component 4.

It can present with lupus-like symptoms.