Hemolytic disease of the newborn (anti-Rhc) can range from a mild to a severe disease. It is the third most common cause of severe HDN. Rh disease is the most common and hemolytic disease of the newborn (anti-Kell) is the second most common cause of severe HDN.

It occurs more commonly in women who are Rh D negative.

Hemolytic disease of the newborn (anti-RhE) is caused by the anti-RhE antibody of the Rh blood group system. The anti-RhE antibody can be naturally occurring, or arise following immune sensitization after a blood transfusion or pregnancy.

The anti-RhE antibody is quite common especially in the Rh genotype CDe/CDe; It usually only causes a mild hemolytic disease, but can cause a severe condition in the newborn. It can occur with other antibodies, usually the anti-Rhc antibody, which can also cause a severe hemolytic disease.

One study done by Moran et al., found that titers are not reliable for anti-E. Their most severe case of hemolytic disease of the newborn occurred with titers 1:2. Moran states that it would be unwise routinely to dismiss anti-E as being of little clinical consequence.

Hemolytic disease of the newborn (anti-Kell) is the second most common cause of severe hemolytic disease of the newborn (HDN) after Rh disease. Anti-Kell is becoming relatively more important as prevention of Rh disease is also becoming more effective.

Hemolytic disease of the newborn (anti-Kell) is caused by a mismatch between the Kell antigens of the mother and fetus. About 91% of the population are Kell negative and about 9% are Kell positive. A fraction of a percentage are homozygous for Kell. Therefore, about 4.5% of babies born to a Kell negative mother are Kell positive.

The disease results when maternal antibodies to Kell are transferred to the fetus across the placental barrier, breaching immune privilege. These antibodies can cause severe anemia by interfering with the early proliferation of red blood cells as well as causing alloimmune hemolysis. Very severe disease can occur as early as 20 weeks gestation. Hydrops fetalis can also occur early. The finding of anti-Kell antibodies in an antenatal screening blood test (indirect Coombs test) is an indication for early referral to a specialist service for assessment, management and treatment.

Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis fetalis, is an alloimmune condition that develops in a fetus, when the IgG molecules (one of the five main types of antibodies) produced by the mother pass through the placenta. Among these antibodies are some which attack antigens on the red blood cells in the fetal circulation, breaking down and destroying the cells (hemolysis). The fetus can develop reticulocytosis and anemia. This fetal disease ranges from mild to very severe, and fetal death from heart failure (hydrops fetalis) can occur. When the disease is moderate or severe, many erythroblasts (immature red blood cells) are present in the fetal blood, and so these forms of the disease can be called "erythroblastosis fetalis" (or "erythroblastosis foetalis").

HDFN represents a breach of immune privilege for the fetus or some other form of impairment of the immune tolerance of pregnancy. Various types of HDFN are classified by which alloantigen provokes the response. In order of incidence, the types include ABO, anti-RhD, anti-RhE, anti-Rhc, anti-Rhe, anti-RhC, multiantigen combinations, and anti-Kell.

Rh disease (also known as rhesus isoimmunisation, Rh (D) disease, rhesus incompatibility, rhesus disease, RhD hemolytic disease of the newborn, rhesus D hemolytic disease of the newborn or RhD HDN) is a type of hemolytic disease of the newborn (HDN). The disease ranges from mild to severe, and typically occurs only in some second or subsequent pregnancies of Rh negative women where the fetus's father is Rh positive, leading to a Rh+ pregnancy. During birth, the mother may be exposed to the infant's blood, and this causes the development of antibodies, which may affect the health of subsequent Rh+ pregnancies. In mild cases, the fetus may have mild anaemia with reticulocytosis. In moderate or severe cases the fetus may have a more marked anaemia and erythroblastosis fetalis (hemolytic disease of the newborn). When the disease is very severe it may cause hydrops fetalis or stillbirth.

Rh disease is generally preventable by treating the mother during pregnancy or soon after delivery with an intramuscular injection of anti-RhD immunoglobulin (Rho(D) immune globulin). The RhD protein is coded by the RHD gene.

In ABO hemolytic disease of the newborn (also known as ABO HDN) maternal IgG antibodies with specificity for the ABO blood group system pass through the placenta to the fetal circulation where they can cause hemolysis of fetal red blood cells which can lead to fetal anemia and HDN. In contrast to Rh disease, about half of the cases of ABO HDN occur in a firstborn baby and ABO HDN does not become more severe after further pregnancies.

The ABO blood group system is the best known surface antigen system, expressed on a wide variety of human cells. For Caucasian populations about one fifth of all pregnancies have ABO incompatibility between the fetus and the mother, but only a very small minority develop symptomatic ABO HDN. The latter typically only occurs in mothers of blood group O, because they can produce enough IgG antibodies to cause hemolysis.

Although very uncommon, cases of ABO HDN have been reported in infants born to mothers with blood groups A and B.

Signs of hemolytic disease of the newborn include a positive direct Coombs test (also called direct agglutination test), elevated cord bilirubin, and hemolytic anemia. It is possible for a newborn with this disease to have neutropenia and neonatal alloimmune thrombocytopenia as well.Hemolysis leads to elevated bilirubin levels. After delivery bilirubin is no longer cleared (via the placenta) from the neonate's blood and the symptoms of jaundice (yellowish skin and yellow discoloration of the whites of the eyes) increase within 24 hours after birth. Like other severe neonatal jaundice, there is the possibility of acute or chronic kernicterus, however the risk of kernicterus is higher because of the rapid destruction of blood cells. It is important to note that isoimmunization is a risk factor for neurotoxicity and lowers the level at which kernicterus can occur. Untreated profound anemia can cause high-output heart failure, with pallor, enlarged liver and/or spleen, generalized swelling, and respiratory distress.

HDN can be the cause of hydrops fetalis, an often-severe form of prenatal heart failure that causes fetal edema.

A Rhc negative mother can become sensitised by red blood cell (RBC) Rhc antigens by her first pregnancy with a Rhc positive fetus. The mother can make IgG anti-Rhc antibodies, which are able to pass through the placenta and enter the fetal circulation. If the fetus is Rhc positive alloimmune hemolysis can occur leading to HDN. This is similar as for Rh disease, which is usually caused when a RhD negative mother is sensitised by her first pregnancy with a RhD positive fetus.

Sensitization to Rhc antigens can also be caused by blood transfusion.

Mothers who are negative for the Kell antigen develop antibodies after being exposed to red blood cells that are positive for Kell. Over half of the cases of hemolytic disease of the newborn owing the anti-Kell antibodies are caused by multiple blood transfusions, with the remainder due to a previous pregnancy with a Kell positive baby.

Hemolytic disease of the fetus and newborn (HDN) is a condition where the passage of maternal antibodies results in the hemolysis of fetal/neonatal red cells. The antibodies can be naturally occurring such as anti-A, and anti-B, or immune antibodies developed following a sensitizing event. Isoimmunization occurs when the maternal immune system is sensitized to red blood cell surface antigens. The most common causes of isoimmunization are blood transfusion, and fetal-maternal hemorrhage. The hemolytic process can result in anemia, hyperbilirubinemia, neonatal thrombocytopenia, and neonatal neutropenia. With the use of RhD Immunoprophylaxis, (commonly called Rhogam), the incidence of anti-D has decreased dramatically and other alloantibodies are now a major cause of HDN.

Routine antenatal antibody screening blood tests (indirect Coombs test) do not screen for ABO HDN. If IgG anti-A or IgG anti-B antibodies are found in the pregnant woman's blood, they are not reported with the test results, because they do not correlate well with ABO HDN. Diagnosis is usually made by investigation of a newborn baby who has developed jaundice during the first week of life.

Testing

- Coombs - after birth baby will have a direct coombs test run to confirm antibodies attached to the infant’s red blood cells. This test is run from cord blood. In some cases, the direct coombs will be negative but severe, even fatal HDN can occur. An indirect coombs needs to be run in cases of anti-C, anti-c, and anti-M. Anti-M also recommends antigen testing to rule out the presence of HDN.

- Hgb - the infant’s hemoglobin should be tested from cord blood.

- Reticulocyte count - Reticulocytes are elevated when the infant is producing more blood to combat anemia. A rise in the retic count can mean that an infant may not need additional transfusions. Low retic is observed in infants treated with IUT and in those with HDN from anti-Kell

- Neutrophils - as Neutropenia is one of the complications of HDN, the neutrophil count should be checked.

- Thrombocytes - as thrombocytopenia is one of the complications of HDN, the thrombocyte count should be checked.

- Bilirubin should be tested from cord blood.

- Ferritin - because most infants affected by HDN have iron overload, a ferritin must be run before giving the infant any additional iron.

- Newborn Screening Tests - Transfusion with donor blood during pregnancy or shortly after birth can affect the results of the Newborn Screening Tests. It is recommended to wait and retest 10–12 months after last transfusion. In some cases, DNA testing from saliva can be used to rule out certain conditions.

Blood is generally drawn from the father to help determine fetal antigen status. If he is homozygous for the antigen, there is a 100% chance of all offspring in the pairing to be positive for the antigen and at risk for HDN. If he is heterozygous, there is a 50% chance of offspring to be positive for the antigen. This test can help with knowledge for the current baby, as well as aid in the decision about future pregnancies. With RhD, the test is called the RhD genotype. With RhCE, and Kell antigen it is called an antigen phenotype.

In some cases, the direct coombs will be negative but severe, even fatal HDN can occur. An indirect coombs needs to be run in cases of anti-C, anti-c, and anti-M. Anti-M also recommends antigen testing to rule out the presence of HDN.

- Hgb - the infant’s hemoglobin should be tested from cord blood.

- Reticulocyte count - Reticulocytes are elevated when the infant is producing more blood to combat anemia. A rise in the retic count can mean that an infant may not need additional transfusions. Low retic is observed in infants treated with IUT and in those with HDN from anti-Kell

- Neutrophils - as Neutropenia is one of the complications of HDN, the neutrophil count should be checked.

- Thrombocytes - as thrombocytopenia is one of the complications of HDN, the thrombocyte count should be checked.

- Bilirubin should be tested from cord blood.

- Ferritin - because most infants affected by HDN have iron overload, a ferritin must be run before giving the infant any additional iron.

- Newborn Screening Tests - Transfusion with donor blood during pregnancy or shortly after birth can affect the results of the Newborn Screening Tests. It is recommended to wait and retest 10–12 months after last transfusion. In some cases, DNA testing from saliva can be used to rule out certain conditions.

Acquired hemolytic anemia can be divided into immune and non-immune mediated forms of hemolytic anemia.

Drug induced hemolysis has large clinical relevance. It occurs when drugs actively provoke red blood cell destruction. It can be divided in the following manner:

- Drug-induced autoimmune hemolytic anemia

- Drug-induced nonautoimmune hemolytic anemia

A total of four mechanisms are usually described, but there is some evidence that these mechanisms may overlap.

Antiphospholipid syndrome or antiphospholipid antibody syndrome (APS or APLS), is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies. APS provokes blood clots (thrombosis) in both arteries and veins as well as pregnancy-related complications such as miscarriage, stillbirth, preterm delivery, and severe preeclampsia.

The diagnostic criteria require one clinical event (i.e. thrombosis or pregnancy complication) and two antibody blood tests spaced at least three months apart that confirm the presence of either lupus anticoagulant or anti-β-glycoprotein-I (since β-glycoprotein-I antibodies are a subset of anti-cardiolipin antibodies, an anti-cardiolipin assay can be performed as a less specific proxy).

Antiphospholipid syndrome can be primary or secondary. Primary antiphospholipid syndrome occurs in the absence of any other related disease. Secondary antiphospholipid syndrome occurs with other autoimmune diseases, such as systemic lupus erythematosus (SLE). In rare cases, APS leads to rapid organ failure due to generalised thrombosis; this is termed "catastrophic antiphospholipid syndrome" (CAPS or Asherson syndrome) and is associated with a high risk of death.

Antiphospholipid syndrome often requires treatment with anticoagulant medication such as heparin to reduce the risk of further episodes of thrombosis and improve the prognosis of pregnancy. Warfarin/Coumadin is not used during pregnancy because it can cross the placenta, unlike heparin, and is teratogenic.

Autoimmune hepatitis, formerly called lupoid hepatitis, is a chronic, autoimmune disease of the liver that occurs when the body's immune system attacks liver cells causing the liver to be inflamed. Common initial symptoms include fatigue or muscle aches or signs of acute liver inflammation including fever, jaundice, and right upper quadrant abdominal pain. Individuals with autoimmune hepatitis often have no initial symptoms and the disease is detected by abnormal liver function tests.

Anomalous presentation of MHC class II receptors on the surface of liver cells, possibly due to genetic predisposition or acute liver infection, causes a cell-mediated immune response against the body's own liver, resulting in autoimmune hepatitis. This abnormal immune response results in inflammation of the liver, which can lead to further symptoms and complications such as fatigue and cirrhosis. The disease may occur in any ethnic group and at any age, but is most often diagnosed in patients between age 40 and 50.

The presence of antiphospholipid antibodies (aPL) in the absence of blood clots or pregnancy-related complications does not indicate APS (see below for the diagnosis of APS).

Antiphospholipid syndrome can cause arterial or venous blood clots, in any organ system, or pregnancy-related complications. In APS patients, the most common venous event is deep vein thrombosis of the lower extremities, and the most common arterial event is stroke. In pregnant women affected by APS, there is an increased risk of recurrent miscarriage, intrauterine growth restriction, and preterm birth. A frequent cause of such complications is placental infarctions.

In some cases, APS seems to be the leading cause of mental and/or development retardation in the newborn, due to an aPL-induced inhibition of trophoblast differentiation. The antiphospholipid syndrome responsible for most of the miscarriages in later trimesters seen in concomitant systemic lupus erythematosus and pregnancy.

Other common findings, although not part of the APS classification criteria, are low platelet count, heart valve disease, and livedo reticularis. There are also associations between antiphospholipid antibodies and headaches, migraines, and oscillopsia. Some studies have shown the presence of antiphospholipid antibodies in the blood and spinal fluid of patients with psychological symptoms.

Very few patients with primary APS go on to develop SLE.

Autoimmune hepatitis may present completely asymptomatic (12–35% of the cases), with signs of chronic liver disease, or acute or even fulminant hepatic failure.

People usually present with one or more nonspecific symptoms, sometimes of long lasting duration, as fatigue, general ill health, lethargy, weight loss, mild right upper quadrant pain, malaise, anorexia, nausea, jaundice or arthralgia affecting the small joints. Rarely, rash or unexplained fever may appear. In women, amenorrhoea is a frequent feature. Physical examination may be normal, but it may also reveal signs and symptoms of chronic liver disease. Many people have only laboratory abnormalities as their initial presentation, as unexplained increase in transaminases and are diagnosed during an evaluation for other reasons. Others have already developed cirrhosis at diagnosis.

Autoimmune hepatitis frequently appears associated with other autoimmune conditions, mainly celiac disease, vasculitis, and autoimmune thyroiditis.

MCTD combines features of scleroderma, myositis, systemic lupus erythematosus, and rheumatoid arthritis (with some sources adding polymyositis, dermatomyositis, and inclusion body myositis) and is thus considered an overlap syndrome.

MCTD commonly causes:

- joint pain/swelling,

- malaise,

- Raynaud phenomenon,

- muscle inflammation, and

- sclerodactyly (thickening of the skin of the pads of the fingers)

Megaloblastic anemia (MA) is associated with GSE and is believed to be the result of B and folate deficiency. In GSE, it appears to be associated with the IgA-less phenotype. Unlike other forms of megaloblastic anemia, GSEA MA is not a form of autoimmune gastritis.

Pernicious anemia (PA). Pernicious anemia is associated with GSE and is believed to result primarily from malabsorption phenomena.

Iron-deficiency anemia. Iron-deficiency anemia (IDA) may be the only symptom for CD, detected in subclinical CD and is accompanied by a decrease in serum ferritin levels. This can cause addition problems (see:symptoms of IDA and certain conditions like such as Paterson-Brown Kelly (Plummer-Vinson). Whereas IDA is corrected on GF diet, refractory disease or gluten-sensitive malignancies can cause persistent IDA.

The antiglomerular basement membrane (GBM) antibodies primarily attack the kidneys and lungs, although, generalized symptoms like malaise, weight loss, fatigue, fever, and chills are also common, as are joint aches and pains. 60 to 80% of those with the condition experience both lung and kidney involvement; 20-40% have kidney involvement alone, and less than 10% have lung involvement alone. Lung symptoms usually antedate kidney symptoms and usually include: coughing up blood, chest pain (in less than 50% of cases overall), cough, and shortness of breath. Kidney symptoms usually include blood in the urine, protein in the urine, unexplained swelling of limbs or face, high amounts of urea in the blood, and high blood pressure.

Goodpasture syndrome (GPS) is a rare autoimmune disease in which antibodies attack the basement membrane in lungs and kidneys, leading to bleeding from the lungs and kidney failure. It is thought to attack the alpha-3 subunit of type IV collagen, which has therefore been referred to as Goodpasture's antigen. Goodpasture syndrome may quickly result in permanent lung and kidney damage, often leading to death. It is treated with immunosuppressant drugs such as corticosteroids and cyclophosphamide, and with plasmapheresis, in which the antibodies are removed from the blood.

The disease was first described by an American pathologist Ernest Goodpasture of Vanderbilt University in 1919 and was later named in his honor.

Gluten-sensitive enteropathy–associated conditions are comorbidities or complications of gluten-related gastrointestinal distress (that is, gluten-sensitive enteropathy or GSE). GSE has key symptoms typically restricted to the bowel and associated tissues; however, there are a wide variety of associated conditions. These include bowel disorders (diarrhoea, constipation, irritable bowel), eosinophilic gastroenteritis and increase with coeliac disease (CD) severity. With some early onset and a large percentage of late onset disease, other disorders appear prior to the celiac diagnosis or allergic-like responses (IgE or IgA, IgG) markedly increased in GSE. Many of these disorders persist on a strict gluten-free diet (GF diet or GFD), and are thus independent of coeliac disease after triggering. For example, autoimmune thyroiditis is a common finding with GSE.

However, GSEs' association with disease is not limited to common autoimmune diseases. Coeliac disease has been found at increased frequency on followup to many autoimmune diseases, some rare. Complex causes of autoimmune diseases often demonstrates only weak association with coeliac disease. The frequency of GSE is typically around 0.3 to 1% and lifelong risk of this form of gluten sensitivity increases in age, possibly as high as 2% for people over 60 years of age. This coincides with the period in life when late-onset autoimmune diseases also rise in frequency.

Genetic studies indicate that coeliac disease genetically links to loci shared by linkage with other autoimmune diseases. These linkages may be coincidental with how symptomatic disease is selected from a largely asymptomatic population.

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.

Distinguishing laboratory characteristics are a positive, speckled anti-nuclear antibody and an anti-U1-RNP antibody.