Erythema nodosum is a form of panniculitis characterised by tender red nodules, 1–10 cm, associated with systemic symptoms including fever, malaise, and joint pain. Nodules may become bluish-purple, yellowing, and green, and subside over a period of 2–6 weeks without ulcerating or scarring. Erythema nodosum is associated with infections, including Hepatitis C, EBV and tuberculosis, Crohn's disease and sarcoidosis, pregnancy, medications including sulfonamides, and some cancers, including Non-Hodgkin lymphoma and pancreatic cancer.

Alpha-1 antitrypsin deficiency panniculitis is a panniculitis associated with a deficiency of the α-antitrypsin enzyme.

Signs/symptoms of humoral immune deficiency depend on the cause, but generally include signs of infection such as:

- Sinusitis

- Sepsis

- Skin infection

- Pneumonia

An autoimmune disease is a condition arising from an abnormal immune response to a normal body part. There are at least 80 types of autoimmune diseases. Nearly any body part can be involved. Common symptoms include low grade fever and feeling tired. Often symptoms come and go.

Humoral immune deficiencies are conditions which cause impairment of humoral immunity, which can lead to immunodeficiency. It can be mediated by insufficient number or function of B cells, the plasma cells they differentiate into, or the antibody secreted by the plasma cells. The most common such immunodeficiency is inherited selective IgA deficiency, occurring between 1 in 100 and 1 in 1000 persons, depending on population.They are associated with increased vulnerability to infection, but can be difficult to detect (or asymptomatic) in the absence of infection.They can be associated with increased risk of gastric cancer.

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

Initial skin findings include red-purple, dusky, flat spots known as macules that start on the trunk and spread out from there. These skin lesions then transform into large blisters. The affected skin can then become necrotic or sag from the body and peel off in great swaths.

Nearly all people with TEN have oral, eye and genital involvement as well. Painful crusts and erosions may develop on any mucosal surface. The mouth becomes blistered and eroded, making eating difficult and sometimes necessitating feeding through a nasogastric tube through the nose or a gastric tube directly into the stomach. The eyes can become swollen, crusted, and ulcerated, leading to potential blindness. The most common problem with the eyes is severe conjunctivitis.

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

Pemphigus foliaceus is an autoimmune blistering disease of the skin with characteristic lesions that are scaly, crusted erosions, often on an erythematous base. Mucosal involvement is absent even with widespread disease.

If there is an autoimmune IgG buildup in the epidermis, then nearly all of the antibodies are aimed against desmoglein 1. The effect of the antibodies and the immunological pathway is most likely one of three mechanisms:

- Steric hindrance of the desmoglein 1: The antibody caps off the site for intracellular binding to another keratinocyte.

- Activation of an endocytic pathway: The antibody activates a pathway which causes an internalization of desmogleïn 1, which in turn causes a loss of adhesion.

- Disruption of function: In this case, the antibody blocks the desmoglein 1 from being formed into a desmosome. This in turn causes a loss of adhesion with acantholysis as a result.

The signs and symptoms of DOCK8 deficiency are similar to the autosomal dominant form, STAT3 deficiency. However, in DOCK8 deficiency, there is no skeletal or connective tissue involvement, and affected individuals do not have the characteristic facial features of those with autosomal dominant hyper-IgE syndrome. DOCK8 deficient children often have eczema, respiratory and skin staphylococcus infections.

Beyond these, many other recurrent infections have been observed, including recurrent fungal infections and recurrent viral infections (including molluscum contagiosum, herpes simplex, and herpes zoster), recurrent upper respiratory infection (including "Streptococcus pneumoniae", "Haemophilus influenzae", respiratory syncytial virus, and adenovirus), recurrent sinusitis, recurrent otitis media, mastoiditis, pneumonia, bronchitis with bronchiectasis, osteomyelitis, candidiasis, meningitis (caused by cryptococcus or H. influenzae), pericarditis, salmonella enteritis, and giardiasis. Other dermatologic problems include squamous-cell carcinoma/dysplasia (vulvar, anal, and facial). Immune problems are also common, including autoimmune hemolytic anemia, severe allergies (both food and environmental), asthma, and reactive airway disease. The nervous system may also be affected; observed conditions in DOCK8 deficient people include hemiplegia, ischemic stroke, subarachnoid hemorrhage, and facial paralysis. Vascular complications are common, including aortic aneurysm, cerebral aneurysm, vessel occlusion and underperfusion, and leukocytoclastic vasculitis.

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.

Myeloperoxidase deficiency is an autosomal recessive genetic disorder featuring deficiency, either in quantity or of function, of myeloperoxidase, an enzyme found in certain phagocytic immune cells, especially polymorphonuclear leukocytes.

It can appear similar to chronic granulomatous disease on some screening tests.

An immune disorder is a dysfunction of the immune system. These disorders can be characterized in several different ways:

- By the component(s) of the immune system affected

- By whether the immune system is overactive or underactive

- By whether the condition is congenital or acquired

According to the International Union of Immunological Societies, more than 150 primary immunodeficiency diseases (PIDs) have been characterized. However, the number of acquired immunodeficiencies exceeds the number of PIDs.

It has been suggested that most people have at least one primary immunodeficiency. Due to redundancies in the immune system, though, many of these are never detected.

LRBA deficiency presents as a syndrome of autoimmunity, lymphoproliferation, and humoral immune deficiency. Predominant clinical problems include idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia (AIHA), and an autoimmune enteropathy. Before the discovery of these gene mutations, patients were diagnosed with common variable immune deficiency (CVID), which is characterized by low antibody levels and recurrent infections. Infections mostly affect the respiratory tract, as many patients suffer from chronic lung disease, pneumonias, and bronchiectasis. Lymphocytic interstitial lung disease (ILD) is also observed, which complicates breathing and leads to impairment of lung function and mortality. Infections can also occur at other sites, such as the eyes, skin and gastrointestinal tract. Many patients suffer from chronic diarrhea and inflammatory bowel disease. Other clinical features can include hepatosplenomegaly, reoccurring warts, growth retardation, allergic dermatitis, and arthritis. Notably, LRBA deficiency has also been associated with type 1 diabetes mellitus. There is significant clinical phenotypic overlap with disease caused by CTLA4 haploinsufficiency. Since LRBA loss results in a loss of CTLA4 protein, the immune dysregulation syndrome of LRBA deficient patients can be attributed to the secondary loss of CTLA4. Because the predominant features of the disease include autoantibody-mediated disease (AIHA, ITP), Treg defects (resembling those found in CTLA4 haploinsufficient patients), autoimmune infiltration (of non-lymphoid organs, also resembling that found in CTLA4 haploinsufficient patients), and enteropathy, the disease has been termed LATAIE for LRBA deficiency with autoantibodies, Treg defects, autoimmune infiltration, and enteropathy.

The following symptoms (signs) are consistent with complement deficiency in general:

Patients usually present with systemic symptoms with single or multiorgan dysfunction. Common (and nonspecific) complaints include fatigue, weakness, fever, arthralgias, abdominal pain, hypertension, renal insufficiency, and neurologic dysfunction. The following symptoms should raise a strong suspicion of a vasculitis:

- Mononeuritis multiplex. Also known as asymmetric polyneuropathy, in a non-diabetic this is suggestive of vasculitis.

- Palpable purpura. If patients have this in isolation, it is most likely due to cutaneous leukocytoclastic vasculitis. If the purpura is in combination with systemic organ involvement, it is most likely to be Henoch-Schonlein purpura or microscopic polyarteritis.

- Pulmonary-renal syndrome. Individuals who are coughing up blood and have kidney involvement are likely to have granulomatosis with polyangiitis, microscopic polyangiitis, or anti-GBM disease (Goodpasture's syndrome).

Although MPO deficiency classically presents with immune deficiency (especially candida albicans infections), the majority of individuals with MPO deficiency show no signs of immunodeficiency.

The lack of severe symptoms suggest that role of myeloperoxidase in the immune response must be redundant to other mechanisms of intracellular killing of phagocytosed bacteria.

Patients with MPO deficiency have a respiratory burst with a normal nitro blue tetrazolium (NBT) test because they still have NADPH oxidase activity, but do not form bleach due to their lack of myeloperoxidase activity. This is in contrast to chronic granulomatous disease, in which the NBT test is 'negative' due to the lack of NADPH oxidase activity (positive test result means neutrophils turn blue, negative means nitroblue tetrazolium remains yellow).

Patients with MPO deficiency are at increased risk for systemic candidiasis.

Acquired hypocomplementemia may occur in the setting of bone infections (osteomyelitis), infection of the lining of the heart (endocarditis), and cryoglobulinemia. Systemic lupus erythematosus is associated with low C3 and C4 Membranoproliferative glomerulonephritis usually has low C3.

A diagnosis can only be definitively made after genetic testing to look for a mutation in the "DOCK8" gene. However, it can be suspected with a high IgE level and eosinophilia. Other suggestive laboratory findings include decreased numbers of B cells, T cells, and NK cells; and hypergammaglobulinemia. It can be distinguished from autosomal dominant hyper-IgE (STAT3 deficiency) because people with DOCK8 deficiency have low levels of IgM and an impaired secondary immune response. IgG and IgA levels are usually normal to high. It can be distinguished from the similar X-linked Wiskott–Aldrich syndrome by the presence of thrombocytopenia and the consequent bloody diarrhea, as well as its pattern of inheritance. WHIM syndrome, caused by a mutation in CXCR4, is associated with similar chronic cutaneous viral infections.

The National Institute of Arthritis and Musculoskeletal and Skin Diseases describes it like this:

"Normally, our immune system produces antibodies that attack viruses and harmful bacteria to keep us healthy. In people with pemphigus, however, the immune system mistakenly attacks the cells in the epidermis, or top layer of the skin, and the mucous membranes. The immune system produces antibodies against proteins in the skin known as desmogleins. These proteins form the glue that keeps skin cells attached and the skin intact. When desmogleins are attacked, skin cells separate from each other and fluid can collect between the layers of skin, forming blisters that do not heal. In some cases, these blisters can cover a large area of skin."

Complete or partial deficiency

- "Complete insufficiency" of T cell function can result from hereditary conditions (also called primary conditions) such as severe combined immunodeficiency (SCID), Omenn syndrome, and cartilage–hair hypoplasia.

- "Partial insufficiencies" of T cell function include acquired immune deficiency syndrome (AIDS), and hereditary conditions such as DiGeorge syndrome (DGS), chromosomal breakage syndromes (CBSs), and B-cell and T-cell combined disorders such as ataxia-telangiectasia (AT) and Wiskott–Aldrich syndrome (WAS).

- "Primary (or hereditary) immunodeficiencies" of T cells include some that cause complete insufficiency of T cells, such as severe combined immunodeficiency (SCID), Omenn syndrome, and Cartilage–hair hypoplasia.

- "Secondary causes" are more common than primary ones. Secondary (or acquired) causes are mainly:

LRBA deficiency is a rare genetic disorder of the immune system. This disorder is caused by a mutation in the gene "LRBA". LRBA stands for “Lipopolysaccharide (LPS)-responsive vesicle trafficking, beach- and anchor-containing” gene. This condition is characterized by autoimmunity, lymphoproliferation, and immune deficiency. It was first described by Gabriela Lopez-Herrera from University College London in 2012. Investigators in the laboratory of Dr. Michael Lenardo at National Institute of Allergy and Infectious Diseases, the National Institutes of Health and Dr. Michael Jordan at Cincinnati Children’s Hospital Medical Center later described this condition and therapy in 2015.

HIES often appears early in life with recurrent staphylococcal and candidal infections, pneumonias, and eczematoid skin.

- Autosomal dominant Hyper-IgE Syndrome caused by STAT3 defects, called Job Syndrome, have characteristic facial, dental, and skeletal abnormalities. Patients with STAT3 HIES may have either delay of or failure in shedding of primary teeth. The characteristic facial features are usually set by age 16. These include facial asymmetry, a prominent forehead, deep-set eyes, a broad nasal bridge, a wide, fleshy nasal tip, and mild prognathism. Additionally, facial skin is rough with prominent pores. Finally, some patients with STAT3 HIES have scoliosis, as well as bones that fracture easily.

- Autosomal recessive

LCH provokes a non-specific inflammatory response, which includes fever, lethargy, and weight loss. Organ involvement can also cause more specific symptoms.

- Bone: The most-frequently seen symptom in both unifocal and multifocal disease is painful bone swelling. The skull is most frequently affected, followed by the long bones of the upper extremities and flat bones. Infiltration in hands and feet is unusual. Osteolytic lesions can lead to pathological fractures.

- Skin: Commonly seen are a rash which varies from scaly erythematous lesions to red papules pronounced in intertriginous areas. Up to 80% of LCH patients have extensive eruptions on the scalp.

- Bone marrow: Pancytopenia with superadded infection usually implies a poor prognosis. Anemia can be due to a number of factors and does not necessarily imply bone marrow infiltration.

- Lymph node: Enlargement of the liver in 20%, spleen in 30% and lymph nodes in 50% of Histiocytosis cases.

- Endocrine glands: Hypothalamic pituitary axis commonly involved. Diabetes insipidus is most common. Anterior pituitary hormone deficiency is usually permanent.

- Lungs: some patients are asymptomatic, diagnosed incidentally because of lung nodules on radiographs; others suffer from chronic cough and shortness of breath.

- Less frequently gastrointestinal tract, central nervous system, and oral cavity.